Additional heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists

ABSTRACT

The present invention relates to new compounds of formula I,  
                 
to pharmaceutical formulations containing the compounds, and to the use of the compounds in the prevention and/or treatment of mGluR5 receptor-mediated disorders.

CROSS REFERENCES TO RELATED APPLICATIONS

This Nonprovisional application claims priority under 35 U.S.C. § 119(e)on Nonprovisional application Ser. No. 11/053,752 filed on Feb. 9, 2005,which claims priority on U.S. Provisional Application No. 60/608,960filed on Feb. 18, 2004, the entire contents of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a new class of compounds, topharmaceutical formulations containing said compounds and to the use ofsaid compounds in therapy. The present invention further relates to theprocess for the preparation of said compounds and to new intermediatesprepared therein.

BACKGROUND OF THE INVENTION

Glutamate is the major excitatory neurotransmitter in the mammaliancentral nervous system (CNS). Glutamate produces its effects on centralneurons by binding to and thereby activating cell surface receptors.These receptors have been divided into two major classes, the ionotropicand metabotropic glutamate receptors, based on the structural featuresof the receptor proteins, the means by which the receptors transducesignals into the cell, and pharmacological profiles.

The metabotropic glutamate receptors (mGluRs) are G protein-coupledreceptors that activate a variety of intracellular second messengersystems following the binding of glutamate. Activation of mGluRs inintact mammalian neurons elicits one or more of the following responses:activation of phospholipase C; increases in phosphoinositide (PI)hydrolysis; intracellular calcium release; activation of phospholipaseD; activation or inhibition of adenyl cyclase; increases or decreases inthe formation of cyclic adenosine monophosphate (cAMP); activation ofguanylyl cyclase; increases in the formation of cyclic guanosinemonophosphate (cGMP); activation of phospholipase A₂; increases inarachidonic acid release; and increases or decreases in the activity ofvoltage- and ligand-gated ion channels. Schoepp et al., TrendsPharmacol. Sci. 14:13 (1993), Schoepp, Neurochem. Int. 24:439 (1994),Pin et al., Neuropharmacology 34:1 (1995), Bordi and Ugolini, Prog.Neurobiol. 59:55 (1999).

Molecular cloning has identified eight distinct mGluR subtypes, termedmGluR1 through mGluR8. Nakanishi, Neuron 13:1031 (1994), Pin et al.,Neuropharmacology 34:1 (1995), Knopfel et al., J. Med. Chem. 38:1417(1995). Further receptor diversity occurs via expression ofalternatively spliced forms of certain mGluR subtypes. Pin et al., PNAS89:10331 (1992), Minakami et al., BBRC 199:1136 (1994), Joly et al., J.Neurosci. 15:3970 (1995).

Metabotropic glutamate receptor subtypes may be subdivided into threegroups, Group I, Group II, and Group III mGluRs, based on amino acidsequence homology, the second messenger systems utilized by thereceptors, and by their pharmacological characteristics. Group I mGluRcomprises mGluR1, mGluR5 and their alternatively spliced variants. Thebinding of agonists to these receptors results in the activation ofphospholipase C and the subsequent mobilization of intracellularcalcium.

Neurological, Psychiatric and Pain Disorders

Attempts at elucidating the physiological roles of Group I mGluRssuggest that activation of these receptors elicits neuronal excitation.Various studies have demonstrated that Group I mGluRs agonists canproduce postsynaptic excitation upon application to neurons in thehippocampus, cerebral cortex, cerebellum, and thalamus, as well as otherCNS regions. Evidence indicates that this excitation is due to directactivation of postsynaptic mGluRs, but it also has been suggested thatactivation of presynaptic mGluRs occurs, resulting in increasedneurotransmitter release. Baskys, Trends Pharmacol. Sci. 15:92 (1992),Schoepp, Neurochem. Int. 24:439 (1994), Pin et al., Neuropharmacology34:1(1995), Watkins et al., Trends Pharmacol. Sci. 15:33 (1994).

Metabotropic glutamate receptors have been implicated in a number ofnormal processes in the mammalian CNS. Activation of mGluRs has beenshown to be required for induction of hippocampal long-term potentiationand cerebellar long-term depression. Bashir et al., Nature 363:347(1993), Bortolotto et al., Nature 368:740 (1994), Aiba et al., Cell79:365 (1994), Aiba et al., Cell 79:377 (1994). A role for mGluRactivation in nociception and analgesia also has been demonstrated,Meller et al., Neuroreport 4: 879 (1993), Bordi and Ugolini, Brain Res.871:223 (1999). In addition, mGluR activation has been suggested to playa modulatory role in a variety of other normal processes includingsynaptic transmission, neuronal development, apoptotic neuronal death,synaptic plasticity, spatial learning, olfactory memory, central controlof cardiac activity, waking, motor control and control of thevestibulo-ocular reflex. Nakanishi, Neuron 13: 1031 (1994), Pin et al.,Neuropharmacology 34:1, Knopfel et al., J. Med. Chem. 38:1417 (1995).

Further, Group I metabotropic glutamate receptors and mGluR5 inparticular, have been suggested to play roles in a variety ofpathophysiological processes and disorders affecting the CNS. Theseinclude stroke, head trauma, anoxic and ischemic injuries, hypoglycemia,epilepsy, neurodegenerative disorders such as Alzheimer's disease andpain. Schoepp et al., Trends Pharmacol. Sci. 14:13 (1993), Cunningham etal., Life Sci. 54:135 (1994), Hollman et al., Ann. Rev. Neurosci. 17:31(1994), Pin et al., Neuropharmacology 34:1 (1995), Knopfel et al., J.Med. Chem. 38:1417 (1995), Spooren et al., Trends Pharmacol. Sci. 22:331(2001), Gasparini et al. Curr. Opin. Pharmacol. 2:43 (2002), NeugebauerPain 98:1 (2002). Much of the pathology in these conditions is thoughtto be due to excessive glutamate-induced excitation of CNS neurons.Because Group I mGluRs appear to increase glutamate-mediated neuronalexcitation via postsynaptic mechanisms and enhanced presynapticglutamate release, their activation probably contributes to thepathology. Accordingly, selective antagonists of Group I mGluR receptorscould be therapeutically beneficial, specifically as neuroprotectiveagents, analgesics or anticonvulsants.

Recent advances in the elucidation of the neurophysiological roles ofmetabotropic glutamate receptors generally and Group I in particular,have established these receptors as promising drug targets in thetherapy of acute and chronic neurological and psychiatric disorders andchronic and acute pain disorders. Because of their physiological andpathophysiological significance, there is a need for new potent mGluRagonists and antagonists that display a high selectivity for mGluRsubtypes, particularly the Group I receptor subtype, most particularlythe mGluR5 subtype.

Gastro Intestinal Disorders

The lower esophageal sphincter (LES) is prone to relaxingintermittently. As a consequence, fluid from the stomach can pass intothe esophagus since the mechanical barrier is temporarily lost at suchtimes, an event hereinafter referred to as “G.I. reflux”.

Gastro-esophageal reflux disease (GERD) is the most prevalent uppergastrointestinal tract disease. Current pharmacotherapy aims at reducinggastric acid secretion, or at neutralizing acid in the esophagus. Themajor mechanism behind G.I. reflux has been considered to depend on ahypotonic lower esophageal sphincter. However, e.g. Holloway & Dent(1990) Gastroenterol. Clin. N. Amer. 19, pp. 517-535, has shown thatmost reflux episodes occur during transient lower esophageal sphincterrelaxations (TLESRs), i.e. relaxations not triggered by swallows. It hasalso been shown that gastric acid secretion usually is normal inpatients with GERD.

The novel compounds according to the present invention are assumed to beuseful for the inhibition of transient lower esophageal sphincterrelaxations (TLESRs) and thus for treatment of gastro-esophageal refluxdisorder (GERD).

The wording “TLESR”, transient lower esophageal sphincter relaxations,is herein defined in accordance with Mittal, R. K., Holloway, R. H.,Penagini, R., Blackshaw, L. A., Dent, J., 1995; Transient loweresophageal sphincter relaxation. Gastroenterology 109, pp. 601-610.

The wording “G.I. reflux” is herein defined as fluid from the stomachbeing able to pass into the esophagus, since the mechanical barrier istemporarily lost at such times.

The wording “GERD”, gastro-esophageal reflux disease, is herein definedin accordance with van Heerwarden, M. A., Smout A. J. P. M., 2000;Diagnosis of reflux disease. Baillière's Clin. Gastroenterol. 14, pp.759-774.

Because of their physiological and pathophysiological significance,there is a need for new potent mGluR agonists and antagonists thatdisplay a high selectivity for mGluR subtypes, particularly the Group Ireceptor subtype.

The object of the present invention is to provide compounds exhibitingan activity at metabotropic glutamate receptors (mGluRs), especially atthe mGluR5 receptor.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula Ia

wherein:

P is selected from the group consisting of hydrogen, C₃₋₇alkyl or a 3-to 8-membered ring containing one or more atoms independently selectedfrom C, N, O and S, which ring may optionally be fused with a 5- or6-membered ring containing one or more atoms independently selected fromthe group consisting of C, N, O and S;

R¹ is selected from the group consisting of hydrogen, hydroxy, halo,nitro, C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl,C₂₋₆alkenyl, OC₂₋₆alkenyl, C₂₋₆alkynyl, OC₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, OC₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,OC₀₋₆alkylaryl, CHO, (CO)R⁵, O(CO)R⁵, O(CO)OR, O(CN)OR⁵, C₁₋₆alkylOR⁵,OC₂₋₆alkylOR⁵, C₁₋₆alkyl(CO)R⁵, OC₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵,OC₁₋₆alkylCO₂R⁵, C₀₋₆alkylcyano, OC₂₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶,OC₂₋₆alkylNR⁵R⁶, C₁₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶,C₀₋₆alkylNR⁵(CO)R⁶, OC₂₋₆alkylNR⁵(CO)R⁶, C₁₋₆alkylNR⁵(CO)NR⁵R⁶,C₀₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵,C₀₋₆alkylSO₂R⁵, OC₂₋₆alkylSO₂R⁵, C₀₋₆alkyl(SO₂)NR⁵R⁶,OC₂₋₆alkyl(SO₂)NR⁵R⁶, C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶,C₀₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkylNR⁵(SO₂)NR⁵R⁶, (CO)NR⁵R⁶, O(CO)NR⁵R⁶,NR⁵OR⁶, C₀₋₆alkylNR⁵(CO)OR⁶, OC₂₋₆alkylNR⁵(CO)OR⁶, SO₃R⁵ and a 5- or6-membered ring containing one or more atoms independently selected fromthe group consisting of C, N, O and S, wherein said ring may besubstituted by one or more A;

M¹ is selected from the group consisting of a bond, C₁₋₃alkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl, C₀₋₃alkylOC₀₋₃alkyl,C₀₋₃alkyl(CO)NR⁵, C₀₋₃alkyl(CO)NR⁵C₀₋₃alkyl, C₀₋₄alkylNR⁵,C₀₋₃alkylSC₀₋₃alkyl, C₀₋₃alkyl(SO)C₀₋₃alkyl or C₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R² is selected from the group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,O(CO)C₁₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl,(SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ andC₀₋₄alkylNR⁵R⁶;

X¹, X² and X³ are independently selected from the group consisting ofCR, CO, N, NR, O and S;

R is selected from the group consisting of hydrogen, C₀₋₃alkyl, halo,C₀₋₃alkylOR⁵, C₀₋₃alkylNR⁵R⁶, C₀₋₃alkyl(CO)OR⁵, C₀₋₃alkylNR⁵R⁶ andC₀₋₃alkylaryl;

M² is selected from a group consisting of a bond, C₁₋₃alkyl,C₃₋₇cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl,C₀₋₃alkylOC₀₋₃alkyl, C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵,C₀₋₄alkylNR⁵, C₀₋₃alkylSC₀₋₃alkyl, C₀₋₃alkyl(SO)C₀₋₃alkyl andC₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R³ is selected from a group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,O(CO)C₁₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl,(SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ andC₀₋₄alkylNR⁵R⁶;

X⁴ is selected from the group consisting of C₀₋₄alkylR⁵,C₀₋₄alkyl(NR⁵R⁶), C₀₋₄alkyl(NR⁵R⁶)═N, NR⁵C₀₋₄alkyl(NR⁵R⁶)═N,NOC₀₋₄alkyl, C₁₋₄alkylhalo, C, O, SO, SO₂ and S;

Q is a 5- or 6-membered ring containing one or more atoms independentlyselected from the group consisting of C, N, O and S, which group mayoptionally be fused with a 5- or 6-membered ring containing one or moreatoms independently selected from the group consisting of C, N, O and Sand which fused ring may be substituted by one or more A;

R⁴ is selected from the group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,OC₁₋₄alkyl, OC₀₋₆alkylaryl, O(CO)C₁₋₄alkyl, C₀₋₄alkyl(S)C₀₋₄alkyl,C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,(SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵, C₀₋₄alkylNR⁵R⁶ and a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O or S,wherein said ring may be substituted by one or more A;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, hydroxy, C₁₋₆alkyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl and a 5- or 6-membered ring containing one or moreatoms independently selected from C, N, O and S, and wherein R⁵ and R⁶may together form a 5- or 6-membered ring containing one or more atomsindependently selected from the group consisting of C, N, O and S;

wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl and C₀₋₆alkylheteroaryl definedunder R¹, R², R³R⁴, R⁴ and R⁵ may be substituted by one or more A;

A is selected from the group consisting of hydrogen, hydroxy, oxo, halo,nitro, C₀₋₆alkylcyano, C₁₋₄alkyl, C₀₋₄alkylC₃₋₆cycloalkyl,C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₂₋₆alkenyl, OC₁₋₆alkyl, C₀₋₃alkylaryl,C₀₋₆alkylOR⁵, OC₂₋₆alkylOR⁵, C₁₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, (CO)R⁵,O(CO)R⁵, OC₂₋₆alkylcyano, C₀₋₆alkylCO₂R⁵, OC₁₋₆alkylCO₂R⁵, O(CO)OR⁵,OC₁₋₆alkyl(CO)R⁵, C₁₋₆alkyl(CO)R⁵, NR⁵OR⁶, C₀₋₆alkylNR⁵R⁶,OC₂₋₆alkylNR⁵R⁶, C₀₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶,OC₂₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)NR⁵R⁶,O(CO)NR⁵R⁶, NR⁵(CO)OR⁶, C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶,C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, SO₃R⁵,C₁₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)R⁵, C₀₋₆alkyl(SO₂)R⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵ and a 5- or 6-membered ring containingone or more atoms independently selected from the group consisting of C,N, O and S;

m is selected from 0, 1, 2, 3 and 4; and

n is selected from 0, 1, 2 and 3,

or salt thereof.

The present invention provides a compound of formula I

wherein:

P is selected from the group consisting of thiophene, pyridyl,thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring issubstituted on position 3 or disubstituted on positions 2 and 5;

R¹ is attached to P via a carbon atom on ring P and is selected from thegroup consisting of hydrogen, hydroxy, halo, nitro, C₁₋₆alkylhalo,OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl, OC₂₋₆alkenyl,C₂₋₆alkynyl, OC₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl,OC₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, OC₀₋₆alkylaryl, CHO,(CO)R⁵O(CO)R⁵, O(CO)OR⁵, O(CN)OR⁵, C₁₋₆alkylOR⁵, OC₂₋₆alkylOR⁵,C₁₋₆alkyl(CO)R⁵, OC₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵, OC₁₋₆alkylCO₂R⁵,C₀₋₆alkylcyano, OC₂₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶, OC₂₋₆alkylNR⁵R⁶,C₁₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶, C₀₋₆alkylNR⁵ (CO)R⁶,OC₂₋₆alkylNR⁵ (CO)R⁶, C₀₋₆alkylNR⁵(CO)NR⁵R⁶, C₀₋₆alkylSR⁵,OC₂₋₆alkylSR⁵, C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵, C₀₋₆alkylSO₂R⁵,OC₂₋₆alkylSO₂R⁵, C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶,C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, C₀₋₆alkylNR⁵(SO₂)NR⁵R⁶,OC₂₋₆alkylNR⁵(SO₂)NR⁵R⁶, (CO)NR⁵R⁶, O(CO)NR⁵R⁶, NR⁵OR⁶,C₀₋₆alkylNR⁵(CO)OR⁶, OC₂₋₆alkylNR⁵(CO)OR⁶, SO₃R⁵ and a 5- or 6-memberedring containing one or more atoms independently selected from the groupconsisting of C, N, O and S;

M¹ is a bond;

X¹ selected from the group consisting of C, CO, N, O and S;

X² is selected from the group consisting of C, N, O and S;

X³ is i) selected from the group consisting of N, O and S, or

ii) selected from N, O, S, and C when X² is selected from N, O, or S,and when X³ is C the substituent R on X³ is H;

R is selected from the group consisting of hydrogen, C₀₋₃alkyl, halo,C₀₋₃alkylOR⁵, C₀₋₃alkylNR⁵R⁶, C₀₋₃alkyl(CO)OR⁵ and C₀₋₃alkylaryl;

M² is selected from a group consisting of a bond, C₁₋₃alkyl,C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl, C₀₋₃alkylOC₀₋₃alkyl,C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵, C₀₋₄alkylNR⁵,C₀₋₃alkyl(SO)C₀₋₃alkyl and C₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R³ is selected from a group consisting of hydroxy, C₀₋₆alkylcyano, oxo,═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl, O(CO)C₁₋₄alkyl,C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,(SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ and C₀₋₄alkylNR⁵R⁶;

X⁴ is selected from the group consisting of C₀₋₄alkylR⁵R⁶,C₃₋₇cycloalkyl, C₁₋₄alkyl(NR⁵R⁶), NR⁵, C₀₋₄alkyl(NR⁵R⁶)═N,NR⁵C₀₋₄alkyl(NR⁵R⁶)═N, NOC₀₋₄alkyl, C₁₋₄alkylhalo, O, SO, SO₂ and S, andwherein the bond between M² and X⁴ is a single bond;

Q is i) selected from the group consisting of triazolyl, imidazolyl,oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl andthiadiazolyl, and wherein any substitutable nitrogen atom in the ring issubstituted with R⁴ on such nitrogen atom and any suitable carbon atomis optionally substituted with R⁴; and

-   -   R⁴ is selected from the group consisting of C₀₋₆alkylcyano,        ═NC₁₋₄alkyl, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₆alkyl, OC₁₋₄alkyl,        C₂₋₄alkenyl, C₀₋₂alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,        C₀₋₆alkylheteroaryl, OC₀₋₆alkylaryl, OC₀₋₆alkylheteroaryl,        NC₀₋₆alkylaryl, NC₀₋₆alkylheteroaryl, C₀₋₆alkylOaryl,        C₀₋₆alkylOheteroaryl, C₀₋₆alkylNaryl, C₀₋₆alkylNheteroaryl,        OC₀₋₆alkylOaryl, OC₀₋₆alkylOheteroaryl, OC₀₋₆alkylNaryl,        OC₀₋₆alkylNheteroaryl, NC₀₋₆alkylOaryl, NC₀₋₆alkylOheteroaryl,        NC₀₋₆alkylNaryl, NC₀₋₆alkylNheteroaryl, O(CO)C₁₋₄alkyl,        C₀₋₄alkyl(CO)OC₁₋₄alkyl, C₁₋₄alkyl(S)C₀₋₄alkyl,        C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,        (SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵, C₀₋₄alkylN(C₁₋₄alkyl)₂ and a 3- or        6-membered non-aromatic ring containing one or more atoms        independently selected from C, N, O and S, which ring may        optionally be fused with a 5-membered ring containing one or        more atoms independently selected from the group consisting of        C, N and O and wherein said ring and said fused ring may be        substituted by one or two A; or

ii) selected from the group consisting of benzoimidazolyl,benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl,imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl;and

-   -   R⁴ is selected from the group consisting of hydrogen, hydroxy,        C₀₋₆alkylcyano, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₆alkyl,        OC₁₋₄alkyl, OC₀₋₆alkylaryl, O(CO)C₁₋₄alkyl,        C₀₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl,        C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl,        C₁₋₄alkylOR⁵, C₀₋₄alkylNR⁵R⁶ and a 5- or 6-membered ring        containing one or more atoms independently selected from C, N, O        and S, which ring may optionally be fused with a 5- or        6-membered ring containing one or more atoms independently        selected from the group consisting of C, N and O and wherein        said ring and said fused ring may be substituted by one or two        A;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen and C₁₋₆alkyl;

wherein any C₁₋₆alkyl defined under R¹, R² and R⁴ may be substituted byone or more A;

A is selected from the group consisting of hydrogen, hydroxy, halo,nitro, oxo, C₀₋₆alkylcyano, C₀₋₄alkylC₃₋₆cycloalkyl, C₁₋₆alkyl,C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₂₋₆alkenyl, C₀₋₃alkylaryl, C₀₋₆alkylOR⁵,OC₂₋₆alkylOR⁵, C₁₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, (CO)R⁵, O(CO)R⁵,OC₂₋₆alkylcyano, OC₁₋₆alkylCO₂R⁵, O(CO)OR⁵, OC₁₋₆alkyl(CO)R⁵,C₁₋₆alkyl(CO)R⁵, NR⁵OR⁶, OC₂₋₆alkylNR⁵R⁶, C₀₋₆alkyl(CO)NR⁵R⁶,OC₁₋₆alkyl(CO)NR⁵R⁶, OC₂₋₆alkylNR⁵ (CO)R⁶, C₀₋₆alkylNR⁵(CO)R⁶,C₀₋₁alkylNR⁵(CO)NR⁵R⁶, O(CO)NR⁵R⁶, C₀₋₆alkyl(SO₂)NR⁵R⁶,OC₂₋₆alkyl(SO₂)NR⁵R⁶, C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, SO₃R⁵,C₁₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)R⁵, C₀₋₆alkyl(SO₂)R⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵ and a 5-membered ring containing oneor more atoms independently selected from the group consisting of C, N,O and S;

m1 is selected from 0, 1, 2, 3 and 4;

m2 is selected from 0, 1, 2 and 3;

n is selected from 0, 1 and 2; and

t is 0 or 1,

and salts thereof,

with the proviso that the compound is not5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole,1,2-di{2-(3-amino-phenyl)-[1,3,4]oxadiazole-yl)ethane, 1,2-di{5-[5-(4-nitro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane,1,2-di{5-[5-(4-bromo-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane,1,2-di{5-[5-(4-chloro-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane and1,2-di {5-[5-(2,4-dibromo-phenyl)furan-2-yl]-[1,3,4]oxadiazol-yl)ethane.

The present invention provides a compound of formula Ib

wherein:

P is selected from the group consisting of thiophene, pyridyl,thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring issubstituted on position 3 or disubstituted on positions 2 and 5;

R¹ is attached to P via a carbon atom on ring P and is selected from thegroup consisting of hydrogen, hydroxy, halo, nitro, C₁₋₆alkylhalo,OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl, OC₂₋₆alkenyl,C₂₋₆alkynyl, OC₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl,OC₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, OC₀₋₆alkylaryl, CHO, (CO)R⁵,O(CO)R⁵, O(CO)OR⁵, O(CN)OR⁵, C₁₋₆alkylOR⁵, OC₂₋₆alkylOR⁵,C₁₋₆alkyl(CO)R⁵, OC₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵, OC₁₋₆alkylCO₂R⁵,C₀₋₆alkylcyano, OC₂₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶, OC₂₋₆alkylNR⁵R⁶,C₁₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶, C₀₋₆alkylNR⁵(CO)R⁶,OC₂₋₆alkylNR⁵ (CO)R⁶, C₀₋₆alkylNR⁵(CO)NR⁵R⁶, C₀₋₆alkylSR⁵,OC₂₋₆alkylSR⁵, C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵, C₀₋₆alkylSO₂R⁵,OC₂₋₆alkylSO₂R⁵, C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶,C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, C₀₋₆alkylNR⁵(SO₂)NR⁵R⁶,OC₂₋₆alkylNR⁵(SO₂)NR⁵R⁶, (CO)NR⁵R⁶, O(CO)NR⁵R⁶, NR⁵OR⁶,C₀₋₆alkylNR⁵(CO)OR⁶, OC₂₋₆alkylNR⁵(CO)OR⁶, SO₃R⁵ and a 5- or 6-memberedring containing one or more atoms independently selected from the groupconsisting of C, N, O and S;

M¹ is a bond;

X¹ selected from the group consisting of C, CO, N, O and S;

X² is selected from the group consisting of C, N, O and S;

X³ is selected from the group consisting of N, O and S, or X³ is CH whenX² is N, O or S;

R is selected from the group consisting of hydrogen, C₀₋₃alkyl, halo,C₀₋₃alkylOR⁵, C₀₋₃alkylNR⁵R⁶, C₀₋₃alkyl(CO)OR⁵ and C₀₋₃alkylaryl;

M² is selected from a group consisting of a bond, C₁₋₃alkyl,C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl, C₀₋₃alkylOC₀₋₃alkyl,C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵, C₀₋₄alkylNR⁵,C₀₋₃alkyl(SO)C₀₋₃alkyl and C₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R³ is selected from a group consisting of hydroxy, C₀₋₆alkylcyano, oxo,═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl, O(CO)C₁₋₄alkyl,C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,(SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ and C₀₋₄alkylNR⁵R⁶;

X⁴ is selected from the group consisting of C₀₋₄alkylR⁵R⁶,C₃₋₇cycloalkyl, C₁₋₄alkyl(NR⁵R⁶), NR⁵, C₀₋₄alkyl(NR⁵R⁶)═N,NR⁵C₀₋₄alkyl(NR⁵R⁶)═N, NOC₀₋₄alkyl, C₁₋₄alkylhalo, O, SO, SO₂ and S, andwherein the bond between M² and X⁴ is a single bond;

Q is i) selected from the group consisting of triazolyl, imidazolyl,oxadiazolyl, imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl andthiadiazolyl, and wherein any substitutable nitrogen atom in the ring issubstituted with R⁴ on such nitrogen atom; and

-   -   R⁴ is selected from the group consisting of C₀₋₆alkylcyano,        ═NC₁₋₄alkyl, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₆alkyl, OC₁₋₄alkyl,        C₂₋₄alkenyl, C₀₋₂alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,        C₀₋₆alkylheteroaryl, OC₀₋₆alkylaryl, OC₀₋₆alkylheteroaryl,        NC₀₋₆alkylaryl, NC₀₋₆alkylheteroaryl, C₀₋₆alkylOaryl,        C₀₋₆alkylOheteroaryl, C₀₋₆alkylNaryl, C₀₋₆alkylNheteroaryl,        OC₀₋₆alkylOaryl, OC₀₋₆alkylOheteroaryl, OC₀₋₆alkylNaryl,        OC₀₋₆alkylNheteroaryl, NC₀₋₆alkylOaryl, NC₀₋₆alkylOheteroaryl,        NC₀₋₆alkylNaryl, NC₀₋₆alkylNheteroaryl, O(CO)C₁₋₄alkyl,        C₀₋₄alkyl(CO)OC₁₋₄alkyl, C₁₋₄alkyl(S)C₀₋₄alkyl,        C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,        (SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵, C₀₋₄alkylN(C₁₋₄alkyl)₂ and a 3- or        6-membered non-aromatic ring containing one or more atoms        independently selected from C, N, O and S, which ring may        optionally be fused with a 5-membered ring containing one or        more atoms independently selected from the group consisting of        C, N and O and wherein said ring and said fused ring may be        substituted by one or two A; or

ii) selected from the group consisting of benzoimidazolyl,benzooxazolyl, tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl,pyridonyl, pyridazinyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl,imidazopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl and purinyl;and

-   -   R⁴ is selected from the group consisting of hydrogen, hydroxy,        C₀₋₆alkylcyano, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₆alkyl,        OC₁₋₄alkyl, OC₀₋₆alkylaryl, O(CO)C₁₋₄alkyl,        C₀₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl,        C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl,        C₁₋₄alkylOR⁵, C₀₋₄alkylNR⁵R⁶ and a 5- or 6-membered ring        containing one or more atoms independently selected from C, N, O        and S, which ring may optionally be fused with a 5- or        6-membered ring containing one or more atoms independently        selected from the group consisting of C, N and O and wherein        said ring and said fused ring may be substituted by one or two        A;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen and C₁₋₆alkyl;

wherein any C₁₋₆alkyl defined under R¹, R² and R⁴ may be substituted byone or more A;

A is selected from the group consisting of hydrogen, hydroxy, halo,nitro, oxo, C₀₋₆alkylcyano, C₀₋₄alkylC₃₋₆cycloalkyl, C₁₋₆alkyl,C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₂₋₆alkenyl, C₀₋₃alkylaryl, C₀₋₆alkylOR⁵,OC₂₋₆alkylOR⁵, C₁₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, (CO)R⁵, O(CO)R⁵,OC₂₋₆alkylcyano, OC₁₋₆alkylCO₂R⁵, O(CO)OR⁵, OC₁₋₆alkyl(CO)R⁵,C₁₋₆alkyl(CO)R⁵, NR⁵OR⁶, OC₂₋₆alkylNR⁵R⁶, C₀₋₆alkyl(CO)NR⁵R⁶,OC₁₋₆alkyl(CO)NR⁵R⁶, OC₂₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)R⁶,C₀₋₆alkylNR⁵(CO)NR⁵R⁶, O(CO)NR⁵R⁶, C₀₋₆alkyl(SO₂)NR⁵R⁶,OC₂₋₆alkyl(SO₂)NR⁵R⁶, C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, SO₃R⁵,C₁₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)R⁵, C₀₋₆alkyl(SO₂)R⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵ and a 5-membered ring containing oneor more atoms independently selected from the group consisting of C, N,O and S;

m1 is selected from 0, 1, 2, 3 and 4;

m2 is selected from 0, 1, 2 and 3;

n is selected from 0, 1 and 2; and

t is 0 or 1,

and salts thereof,

with the proviso that the compound is not5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole.

In a further aspect of the invention there is provided pharmaceuticalformulations comprising a therapeutically effective amount of a compoundof formula I and a pharmaceutically acceptable carrier.

In yet a further aspect of the invention there is provided apharmaceutical formulation including a compound of formula I for use inthe treatment of mGluR5 receptor-mediated disorders, and particularlyneurological disorders, psychiatric disorders, acute and chronic pain,and gastrointestinal disorders.

In still a further aspect of the invention there is provided a compoundof formula I for use in therapy for the treatment of mGluR5receptor-mediated disorders, and particularly neurological disorders,psychiatric disorders, acute and chronic pain, and gastrointestinaldisorders.

In another aspect of the invention there is provided a process for thepreparation of compounds of formula I, and the intermediates providedtherein.

These and other aspects of the present invention are described ingreater detail herein below.

DETAILED DESCRIPTION OF THE INVENTION

Listed below are definitions of various terms used in the specificationand claims to describe the present invention.

For the avoidance of doubt it is to be understood that where in thisspecification a group is qualified by ‘hereinbefore defined’, ‘definedhereinbefore’ or ‘defined above’ the said group encompasses the firstoccurring and broadest definition as well as each and all of the otherdefinitions for that group.

For the avoidance of doubt it is to be understood that in thisspecification ‘C₁₋₆’ means a carbon group having 1, 2, 3, 4, 5 or 6carbon atoms.

In this specification “C” means 1 carbon atom.

In this specification, unless stated otherwise, the term “alkyl”includes both straight and branched chain alkyl groups and may bemethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,

s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl ori-hexyl, t-hexyl. The term “C₁₋₃alkyl” refers to an alkyl group having1, 2 or 3 carbon atoms, and may be methyl, ethyl, n-propyl and i-propyl.

In this specification, unless stated otherwise, the term “cycloalkyl”refers to an optionally substituted, saturated cyclic hydrocarbon ringsystem. The term “C₃₋₇cycloalkyl” may be cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and cycloheptyl.

In this specification, unless stated otherwise, the term “alkenyl”includes both straight and branched chain alkenyl groups. The term“C₂₋₆alkenyl” refers to an alkenyl group having 2 to 6 carbon atoms andone or two double bonds, and may be, but is not limited to vinyl, allyl,propenyl, i-propenyl, butenyl, i-butenyl, crotyl, pentenyl, i-pentenyland hexenyl.

In this specification, unless stated otherwise, the term “alkynyl”includes both straight and branched chain alkynyl groups. The termC₂₋₆alkynyl having 2 to 6 carbon atoms and one or two triple bonds, andmay be, but is not limited to ethynyl, propargyl, butynyl, i-butynyl,pentynyl, i-pentynyl and hexynyl.

The term “aryl” refers to an optionally substituted monocyclic orbicyclic hydrocarbon ring system containing at least one unsaturatedaromatic ring. Examples and suitable values of the term “aryl” arephenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, indyl and indenyl.

In this specification, unless stated otherwise, the term “heteroaryl”refer to an optionally substituted monocyclic or bicyclic unsaturated,aromatic ring system containing at least one heteroatom selectedindependently from N, O or S. Examples of “heteroaryl” may be, but arenot limited to thiophene, thienyl, pyridyl, thiazolyl, furyl, pyrrolyl,triazolyl, imidazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyrazolyl,imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl,benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,tetrahydrotriazolopyrimidinyl, benzofuryl, indolyl, isoindolyl,pyridonyl, pyridazinyl, pyrimidinyl, imidazopyridyl, oxazolopyridyl,thiazolopyridyl, pyridyl, imidazopyridazinyl, oxazolopyridazinyl,thiazolopyridazinyl and purinyl.

In this specification, unless stated otherwise, the term “alkylaryl”,“alkylheteroaryl” and “alkylcycloalkyl” refer to a substituent that isattached via the alkyl group to an aryl, heteroaryl and cycloalkylgroup.

In this specification, unless stated otherwise, a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O or S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to furyl, isoxazolyl,isothiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, thiazolyl, thienyl, imidazolyl, imidazolidinyl,imidazolinyl, triazolyl, morpholinyl, piperazinyl, piperidyl,piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl,tetrahydropyranyl, thiomorpholinyl, phenyl, cyclohexyl, cyclopentyl andcyclohexenyl.

In this specification, unless stated otherwise, a 3- to 8-membered ringcontaining one or more atoms independently selected from C, N, O or S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to imidazolidinyl, imidazolinyl,morpholinyl, piperazinyl, piperidyl, piperidonyl, pyrazolidinyl,pyrazolinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl orthiomorpholinyl, tetrahydrothiopyranyl, furyl, pyrrolyl, isoxazolyl,isothiazolyl, oxazolyl, oxazolidinonyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, thiazolyl, thienyl,imidazolyl, triazolyl, phenyl, cyclopropyl, aziridinyl, cyclobutyl,azetidinyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl,cycloheptyl, cycloheptenyl, cyclooctyl and cyclooctenyl.

In this specification, unless stated otherwise, a 3- to 8-membered ringcontaining one or more atoms independently selected from C, N, O or S,which group may optionally be fused with a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O or S,includes aromatic and heteroaromatic rings as well as carbocyclic andheterocyclic rings which may be saturated or unsaturated. Examples ofsuch rings may be, but are not limited to naphthyl, norcaryl, chromyl,isochromyl, indanyl, benzoimidazol or tetralinyl, benzooxazolyl,benzothiazolyl, benzofuryl, benzothienyl, benzotriazolyl, indolyl,azaindolyl, indazolyl, indolinyl, isoindolinyl, benzimidazolyl,oxadiazolyl, thiadiazolyl, quinolinyl, quinoxalinyl and benzotriazolyl.

In this specification, unless stated otherwise, the term “═NR⁵” and“═NOR⁵” include imino- and oximogroups carrying an R⁵ substituent andmay be, or be part of, groups including, but not limited to iminoalkyl,iminohydroxy, iminoalkoxy, amidine, hydroxyamidine and alkoxyamidine.

In the case where a subscript is the integer 0 (zero) the group to whichthe subscript refers, indicates that the group is absent, i.e. there isa direct bond between the groups.

In this specification, unless stated otherwise, the term “bond” is asaturated bond.

In this specification, unless stated otherwise, the term “halo” may befluoro, chloro, bromo or iodo.

In this specification, unless stated otherwise, the term “alkylhalo”means an alkyl group as defined above, substituted with one or morehalo. The term “C₁₋₆alkylhalo” may include, but is not limited tofluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl,difluoroethyl and bromopropyl. The term “OC₁₋₆alkylhalo” may include,but is not limited to fluoromethoxy, difluoromethoxy, trifluoromethoxy,fluoroethoxy and difluoroethoxy.

In one embodiments of the invention P may be hydrogen or C₃₋₇ alkyl or Pmay be a 3- to 8-membered ring containing one or more atoms selectedfrom C, N, O or S said ring may be optionally fused with a 5- or6-membered ring containing one or more atoms independently selected fromC, N, O, or S. In a preferred embodiment of the invention P is selectedfrom 5 and 6 membered aromatic and heteroaromatic rings.

In a further preferred embodiment P is selected from thiophene, pyridyl,thiazolyl, furyl, pyrrolyl and phenyl, whereby the phenyl ring issubstituted on position 3 or disubstituted on positions 2 and 5.

In yet a further preferred embodiment of the invention P is phenylsubstituted on position 3 or disubstituted on positions 2 and 5.

P is optionally substituted via a carbon atom with 0, 1, 2, 3 or 4groups R¹, wherein the number of R¹ substituents on the P ring isdesignated by the term m1. In preferred embodiments of the invention m1is 1 or 2. In further preferred embodiments of the invention m1 is 1.

In suitable embodiments of invention R¹ is selected from the groupconsisting of hydrogen, hydroxy, halo, nitro, C₁₋₆alkylhalo,OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl, OC₂₋₆alkenyl,C₂₋₆alkynyl, OC₂₋₆alkynyl, C₀₋₆alkylC₃₋₆cycloalkyl,OC₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, OC₀₋₆alkylaryl, CHO, (CO)R⁵,O(CO)R⁵, O(CO)OR⁵, O(CN)OR⁵, C₁₋₆alkylOR⁵, OC₂₋₆alkylOR⁵,C₁₋₆alkyl(CO)R⁵, OC₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵, OC₁₋₆alkylCO₂R⁵,C₀₋₆alkylcyano, OC₂₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶, OC₂₋₆alkylNR⁵R⁵,C₁₋₆alkyl(CO)NR⁵R⁶, OC₁₋₃alkyl(CO)NR⁵R⁶, C₀₋₆alkylNR⁵(CO)R⁶,OC₂₋₆alkylNR⁵(CO)R⁶, C₂₋₆alkylNR⁵(CO)NR⁵R⁶, C₀₋₆alkylSR⁵, OC₂₋₆alkylSR⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵, C₀₋₆alkylSO₂R⁵, OC₂₋₆alkylSO₂R⁵,C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶, C₀₋₆alkylNR⁵(SO₂)R⁶,OC₂₋₆alkylNR⁵(SO₂)R⁶, C₀₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkylNR⁵(SO₂)NR⁵R⁶,(CO)NR⁵R⁶, O(CO)NR⁵R⁶, NR⁵OR⁶, C₀₋₆alkylNR⁵(CO)OR⁶,OC₂₋₆alkylNR⁵(CO)OR⁶, SO₃R⁵ and a 5- or 6-membered ring containing oneor more atoms independently selected from the group consisting of C, N,O and S.

In a more suitable embodiment of the invention R¹ is selected fromhydrogen, hydroxy, halo, nitro, C₁₋₆alkylhalo, OC₁₋₆alkylhalo,C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl, C₀₋₆alkylC₃₋₆cycloalkyl,C₁₋₆alkylOR⁵, C₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵, C₀₋₆alkylcyano,C₀₋₆alkylNR⁵R⁶, C₀₋₆alkylSR⁵ and a 5- or 6-membered ring containing oneor more atoms independently selected from the group consisting of C andO.

Any C₁₋₆alkyl defined under R¹ may be substituted by one or more A. Inone embodiment of the invention R¹ is ethyl and A is hydroxyl.

In a further suitable embodiment of the invention R¹ is selected fromhydrogen, methyl, ethyl, cyclopropyl, hydroxy, methoxy, cyano, fluoro,chloro, bromo, iodo, trifluoromethyl, difluoromethoxy, trifluoromethoxy,amino, nitro, dimethylamino, methylsulfanyl, vinyl, acetyl, formic acidmethyl ester, methoxymethyl, ethanol and furyl.

In a more suitable embodiment of the invention P is selected from thegroup consisting of thiophene, pyridyl, thiazolyl, furyl, pyrrolyl orphenyl, whereby the phenyl ring is substituted on position 3 ordisubstituted on positions 2 and 5 and R¹ is selected from the groupconsisting of hydrogen, hydroxy, halo, nitro, C₁₋₆alkylhalo,OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆alkylOR⁵, C₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵,C₀₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶, C₀₋₆alkylSR⁵ and a 5-membered ringcontaining one or more atoms independently selected from the groupconsisting of C and O.

In a further suitable embodiment of the invention P is phenylsubstituted on position 3 or disubstituted on positions 2 and 5 and R¹is selected from the group consisting of hydrogen, hydroxy, halo, nitro,C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl, C₂₋₆alkenyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₁₋₆alkylOR⁵, C₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵,C₀₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶, C₀₋₆alkylSR⁵ and a 5-membered ringcontaining one or more atoms independently selected from the groupconsisting of C and O.

According to another aspect of the invention the ring P is connected tothe core ring by M¹, wherein M¹ can be a bond directly joining P to thecore ring. M¹ can also be a linker C₁₋₃alkyl.

In a preferred embodiment of the invention M¹ is a bond.

When M¹ is not a direct bond M¹ can be further substituted with 0, 1, 2or 3 substituents R² wherein the number of substituents R² is designatedby the term n. The substituents R² may be selected from hydrogen,hydroxy, oxo, C₁₋₄alkylhalo, halo and C₁₋₄alkyl. In a preferredembodiment of the invention n is 0.

In another aspect of the invention there is provided compounds offormula I wherein X¹ is selected from the group consisting of C, CO, N,O and S. In a further aspect of the invention X² is selected from thegroup consisting of C, N, O and S. In yet a further aspect of theinvention X³ is selected from the group consisting of N, O and S, or X³is selected from N, O, S, and C when X² is selected from N, O, or S, andwhen X³ is C the substituent R on X³ is H.

X¹, X² and X³ can be further substituted with 0, 1 or 2 substituents Rwherein the number of substituents R is designated by the term t. Thesubstituent R may be selected from the group consisting of hydrogen,C₀₋₃alkyl, halo, C₀₋₃alkylOR⁵, C₀₋₃alkylNR⁵R⁶, C₀₋₃alkyl(CO)OR⁵,C₀₋₃alkylNR⁵R⁶ and C₀₋₃alkylaryl. In one embodiment of the invention Ris selected from the group consisting of hydrogen, C₀₋₃alkyl and halo.

In a preferred embodiment of the invention X¹ is C, N or O and R isselected from hydrogen, C₀₋₃alkyl and halo. In one embodiment R isselected from hydrogen, chloro or methyl.

In another preferred embodiment of the invention X¹ is N.

In a suitable embodiment X² is selected from N, O and S, and R ishydrogen. In another embodiment of the invention X³ is N, O or S. In afurther preferred embodiment of the invention X¹ is O and one of X² andX³ is O and the other is N. In yet a further preferred embodiment of theinvention X¹ is N and one of X² and X³ is O and the other is N. In yetanother preferred embodiment of the invention X¹ is C or CR and one ofX² and X³ is O and the other is N.

In another preferred embodiment of the invention X² is O and X³ is N,and in yet another preferred embodiment of the invention X² is N and X³is O.

In a further preferred embodiment of the invention X¹ is O and X² and X³are N.

In another suitable embodiment of the invention the ring containing X¹,X² and X³ forms an oxadiazole, isoxazole, oxazole, chloro-isoxazole or amethyl-isoxazole.

In a preferred embodiment of the invention the ring containing X¹, X²and X³ forms an oxadiazole. In another preferred embodiment of theinvention the ring containing X¹, X² and X³ forms an isoxazole.

The ring containing X¹, X² and X³ should not be further annulated ontoany other ring.

In a suitable embodiment of the invention M² may be a direct bond fromthe core ring to the variable X⁴ or M² may be selected from the groupconsisting of bond, C₁₋₃alkyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl,C₀₋₃alkylOC₀₋₃alkyl, C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵,C₀₋₄alkylNR⁵, C₀₋₃alkyl(SO)C₀₋₃alkyl and C₀₋₃alkyl(SO₂)C₀₋₃alkyl.

In preferred embodiments of the invention M² is a bond or C₁₋₃alkyl. Infurther preferred embodiments of the invention M² is C₁₋₃alkyl,preferably methyl or ethyl.

When M₂ is not a direct bond M² may be further substituted with 0, 1 or2 R³ groups wherein the number of substituents R³ is designated by theterm n. In one embodiment of the invention n is 1 or 2. In anotherembodiment of the invention n is 0.

In a suitable embodiment of the invention R³ is selected from the groupconsisting of R³ is selected from a group consisting of hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,O(CO)C₁₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl,(SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ andC₀₋₄alkylNR⁵R⁶.

In a preferred embodiment R³ is selected from hydrogen and C₁₋₄alkyl,preferably methyl or dimethyl.

In another preferred embodiment M² may be selected from the groupconsisting of a bond, C₁₋₃alkyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl,C₀₋₃alkylOC₀₋₃alkyl, C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵,C₀₋₄alkylNR⁵, C₀₋₃alkyl(SO)C₀₋₃alkyl and C₀₋₃alkyl(SO₂)C₀₋₃alkyl and R³is selected from hydrogen and C₁₋₄alkyl.

In yet another preferred embodiments of the invention M² is a bond orC₁₋₃alkyl and R³ is hydrogen, methyl or dimethyl.

In a further preferred embodiment M² may be selected from the groupconsisting of a bond, methyl and ethyl and R³ is hydrogen, methyl ordimethyl.

In a further embodiment of the invention M² is nitrogen. In yet afurther embodiment of the invention M² is oxygen.

According to another aspect of the invention X⁴ is selected from thegroup consisting of C₀₋₄alkylR⁵R⁶, C₃₋₇cycloalkyl, C₁₋₄alkyl(NR⁵R⁶),NR⁵, C₀₋₄alkyl(NR⁵R⁶)═N, NR⁵C₀₋₄alkyl(NR⁵R⁶)═N, NOC₀₋₄alkyl,C₁₋₄alkylhalo, O, SO, SO₂ and S, and wherein the bond between M² and X⁴is a single bond.

In a preferred embodiment of the invention X⁴ is selected from the groupconsisting of C₀₋₄alkylR⁵R⁶, C₃₋₇cycloalkyl, NR⁵, O, SO, SO₂ and S andR⁵ and R⁶ are independently selected from hydrogen and C₁₋₆alkyl.

In a further preferred embodiment of the invention X⁴ is selected fromthe group consisting of CH₂, CHCH₃, CH(CH₃)₂ and NR⁵. In a furtherpreferred embodiment of the invention X⁴ is NR⁵ and R⁵ is selected fromhydrogen and C₁₋₆alkyl. In a preferred embodiment of the invention R⁵ ismethyl or hydrogen and R⁶ is hydrogen.

In still a further preferred embodiment of the invention X⁴ is O. In yetanother preferred embodiment of the invention X⁴ is S.

It is to be understood that the bond between M² and X⁴ is a single bondin all tautomeric forms.

Embodiments of the present invention include those wherein Q is a 5- or6-membered ring.

When Q is a 5-membered ring, Q is selected from the group consisting ofthe group consisting of triazolyl, imidazolyl, oxadiazolyl,imidazolonyl, oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, andwherein any substitutable nitrogen atom in the ring is substituted withR⁴ on such nitrogen atom.

In one embodiment the 5 membered ring Q is selected from the groupconsisting of triazolyl and thiadiazolyl. In another embodiment the 5membered ring Q is selected from the group consisting of tetrazolyl andoxadiazolyl. In a further embodiment the 5 membered ring Q isimidazolyl.

When Q is a 6-membered ring, Q is selected from the group consisting ofbenzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl,oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,thiazolopyridazinyl and purinyl.

In a preferred embodiment of the invention the 6 membered ring Q isselected from the group consisting of pyridonyl,tetrahydrotriazolopyridyl and tetrahydrotriazolopyrimidinyl. In anotherembodiment the 6 membered ring Q is pyridazinyl. In a further embodimentthe 6 membered ring Q is selected from the group consisting ofbenzoimidazolyl, benzooxazolyl and imidazopyridyl.

Q can be further substituted with 0, 1, 2 or 3 substituents R⁴, whereinthe number of R⁴ substituents is designated by the term m2. In apreferred embodiment m2 is 1 or 2. When Q is a 5-membered ring thesubstituent R⁴ is selected from the group consisting of C₀₋₆alkylcyano,═NC₁₋₄alkyl, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₆alkyl, OC₁₋₄alkyl,C₂₋₄alkenyl, C₀₋₂alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl, OC₀₋₆alkylaryl, OC₀₋₆alkylheteroaryl,NC₀₋₆alkylaryl, NC₀₋₆alkylheteroaryl, C₀₋₆alkylOaryl,C₀₋₆alkylOheteroaryl, C₀₋₆alkylNaryl, C₀₋₆alkylNheteroaryl,OC₀₋₆alkylOaryl, OC₀₋₆alkylOheteroaryl, OC₀₋₆alkylNaryl,OC₀₋₆alkylNheteroaryl, NC₀₋₆alkylOaryl, NC₀₋₆alkylOheteroaryl,NC₀₋₆alkylNaryl, NC₀₋₆alkylNheteroaryl, O(CO)C₁₋₄alkyl,C₀₋₄alkyl(CO)OC₁₋₄alkyl, C₁₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl,C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵,C₀₋₄alkylN(C₁₋₄alkyl)₂ and a 3- or 6-membered non-aromatic ringcontaining one or more atoms independently selected from C, N, O and S,which ring may optionally be fused with a 5-membered ring containing oneor more atoms independently selected from the group consisting of C, Nand O and wherein said ring and said fused ring may be substituted byone or two A.

In a further embodiment of the invention R⁴ on the 5 membered Q ring isselected from the group consisting of C₁₋₄alkylhalo, C₁₋₆alkyl,C₂₋₄alkenyl, C₀₋₂alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl, OC₀₋₆alkylaryl, OC₀₋₆alkylheteroaryl,NC₀₋₆alkylaryl, NC₀₋₆alkylheteroaryl, C₀₋₆alkylOaryl,C₀₋₆alkylOheteroaryl, C₀₋₆alkylNaryl, C₀₋₆alkylNheteroaryl,OC₀₋₆alkylOaryl, OC₀₋₆alkylOheteroaryl, OC₀₋₆alkylNaryl,OC₀₋₆alkylNheteroaryl, NC₀₋₆alkylOaryl, NC₀₋₆alkylOheteroaryl,NC₀₋₆alkylNaryl, NC₀₋₆alkylNheteroaryl, C₀₋₄alkyl(CO)OC₁₋₄alkyl,C₁₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkylOR⁵ and a 3- or 6-membered non-aromaticring containing one or more atoms independently selected from C, N, Oand S, which ring may optionally be fused with a 5-membered ringcontaining one or more atoms independently selected from the groupconsisting of C, N and O and wherein said ring and said fused ring maybe substituted by one or two A.

In one embodiment of the invention Q is selected from the groupconsisting of triazolyl, imidazolyl, oxadiazolyl, imidazolonyl,oxazolonyl, thiazolonyl, tetrazolyl and thiadiazolyl, and wherein anysubstitutable nitrogen atom in the ring is substituted with R⁴ on suchnitrogen atom and R⁴ is selected from the group consisting ofC₁₋₄alkylhalo, C₁₋₆alkyl, C₂₋₄alkenyl, C₀₋₂alkylC₃₋₆cycloalkyl,C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl, OC₀₋₆alkylaryl,OC₀₋₆alkylheteroaryl, NC₀₋₆alkylaryl, NC₀₋₆alkylheteroaryl,C₀₋₆alkylOaryl, C₀₋₆alkylOheteroaryl, C₀₋₆alkylNaryl,C₀₋₆alkylNheteroaryl, OC₀₋₆alkylOaryl, OC₀₋₆alkylOheteroaryl,OC₀₋₆alkylNaryl, OC₀₋₆alkylNheteroaryl, NC₀₋₆alkylOaryl,NC₀₋₆alkylOheteroaryl, NC₀₋₆alkylNaryl, NC₀₋₆alkylNheteroaryl,C₀₋₄alkyl(CO)OC₁₋₄alkyl, C₁₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkylOR⁵ and a 3- or6-membered non-aromatic ring containing one or more atoms independentlyselected from C, N, O and S, which ring may optionally be fused with a5-membered ring containing one or more atoms independently selected fromthe group consisting of C, N and O and wherein said ring and said fusedring may be substituted by one or two A.

In another embodiment of the invention Q selected from the groupconsisting of triazolyl, imidazolyl, oxadiazolyl, tetrazolyl andthiadiazolyl, and wherein any substitutable nitrogen atom in the ring issubstituted with R⁴ on such nitrogen atom and R⁴ is selected from thegroup consisting of C₁₋₄alkylhalo, C₁₋₆alkyl, C₂₋₄alkenyl,C₀₋₂alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl, C₀₋₆alkylheteroaryl,OC₀₋₆alkylaryl, OC₀₋₆alkylheteroaryl, NC₀₋₆alkylaryl,NC₀₋₆alkylheteroaryl, C₀₋₆alkylOaryl, C₀₋₆alkylOheteroaryl,C₀₋₆alkylNaryl, C₀₋₆alkylNheteroaryl, OC₀₋₆alkylOaryl,OC₀₋₆alkylOheteroaryl, OC₀₋₆alkylNaryl, OC₀₋₆alkylNheteroaryl,NC₀₋₆alkylOaryl, NC₀₋₆alkylOheteroaryl, NC₀₋₆alkylNaryl,NC₀₋₆alkylNheteroaryl, C₀₋₄alkyl(CO)OC₁₋₄alkyl, C₁₋₄alkyl(S)C₀₋₄alkyl,C₁₋₄alkylOR⁵ and a 3- or 6-membered non-aromatic ring containing one ormore atoms independently selected from C, N, O and S, which ring mayoptionally be fused with a 5-membered ring containing one or more atomsindependently selected from the group consisting of C, N and O andwherein said ring and said fused ring may be substituted by one or twoA.

When Q is a 6-membered ring the substituent R⁴ is selected from thegroup consisting of hydrogen, hydroxy, C₀₋₆alkylcyano, ═NR⁵, ═NOR⁵,C₁₋₄alkylhalo, halo, C₁₋₆alkyl, OC₁₋₄alkyl, OC₀₋₆alkylaryl,O(CO)C₁₋₄alkyl, C₀₋₄alkyl(S)C₀₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl,C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵,C₀₋₄alkylNR⁵R⁶ and a 5- or 6-membered ring containing one or more atomsindependently selected from C, N, O and S, which ring may optionally befused with a 5- or 6-membered ring containing one or more atomsindependently selected from the group consisting of C, N and O andwherein said ring and said fused ring may be substituted by one or twoA.

In a suitable embodiment of the invention R⁴ on the 6 membered Q ring isselected from hydrogen and C₁₋₆alkyl. In a further embodiment of theinvention R⁴ is hydrogen, methyl, ethyl, propyl, butyl or hexyl.

In a preferred embodiment of the invention Q selected from the groupconsisting of benzoimidazolyl, benzooxazolyl, tetrahydrotriazolopyridyl,tetrahydrotriazolopyrimidinyl, pyridonyl, pyridazinyl, imidazopyridyl,oxazolopyridyl, thiazolopyridyl, imidazopyridazinyl, oxazolopyridazinyl,thiazolopyridazinyl and purinyl and R⁴ is hydrogen or C₁₋₆alkyl.

In another preferred embodiment of the invention Q selected from thegroup consisting of benzoimidazolyl, benzooxazolyl,tetrahydrotriazolopyridyl, tetrahydrotriazolopyrimidinyl, pyridonyl,pyridazinyl and imidazopyridyl, and R⁴ is hydrogen or C₁₋₆alkyl.

In a suitable embodiment of the invention R⁴ is selected from the groupconsisting of benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl,butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol,chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl, cyclopentyl,dichloro-phenyl, dichloropyridyl, difluorophenyl, dimethylthiazolyl,ethanol, ethoxymethyl, fluoromethylphenyl, fluorophenyl, formic acidmethyl ester, furyl, hydrogen, hydroxyphenoxymethyl, hydroxyphenyl,imidazolyl, methoxyethyl, methoxymethyl, methoxyphenoxymethyl,methoxyphenyl, methoxyphenylethyl, methoxypyridazinyl, methoxypyridyl,methoxypyrimidinyl, methoxythiophene, methylimidazolyl, methylpyridyl,methylsulfanylmethyl, methylthiazolyl, methylthiophene, nitrofuryl,nitrophenyl, phenyl, p-tolyloxymethyl, pyridazinyl, pyridine-oxidyl,benzylmorpholinyl, pyridinolyl, pyridyl, pyridylmethyl, pyrimidinyl,tert-butylphenyl, tetrahydrofuryl, thiazolyl, thiophene, tolyl,trifluoromethyl, acetic acid methylester, allyl, amino, benzyl,cyclopropylmethyl, ethyl, fluorobenzyl, fluoroethyl, furylmethyl,hydroxyethyl, isobutyl, methyl, methylbenzyl, methylbutyl,methylsulfanylpropyl, n-butyl, n-hexyl, n-propyl, tetrahydrofurylmethyl,thiophenylmethyl and trifluoroethyl.

Ring Q may be substituted by one or more R⁴ on a carbon and/or anitrogen atom in the ring. When Q is substituted on the carbon atom, R⁴is selected from benzo[b]thiophenyl, benzodioxolyl, bromo, bromofuryl,butoxyphenyl, chloromethoxypyridyl, chlorophenyl, chlorophenylmethanol,chloropyridyl, chlorothiophene, cyanophenyl, cyclohexyl, cyclopentyl,dichloro-phenyl, dichloropyridyl, difluorophenyl, dimethylthiazolyl,ethanol, ethoxymethyl, fluoromethylphenyl, fluorophenyl, formic acidmethyl ester, furyl, hydrogen, hydroxyphenoxymethyl, hydroxyphenyl,imidazolyl, methoxyethyl, methoxymethyl, methoxyphenoxymethyl,methoxyphenyl, methoxyphenylethyl, methoxypyridazinyl, methoxypyridyl,methoxypyrimidinyl, methoxythiophene, methylimidazolyl, methylpyridyl,methylsulfanylmethyl, methylthiazolyl, methylthiophene, nitrofuryl,nitrophenyl, phenyl, p-tolyloxymethyl, pyridazinyl, pyridine-oxidyl,benzylmorpholinyl, pyridinolyl, pyridyl, pyridylmethyl, pyrimidinyl,tert-butylphenyl, tetrahydrofuryl, thiazolyl, thiophene, tolyl andtrifluoromethyl.

When Q is substituted on the nitrogen atom, R⁴ is selected from aceticacid methylester, allyl, amino, benzyl, cyclopropyl, cyclopropylmethyl,ethyl, fluorobenzyl, fluoroethyl, furylmethyl, hydroxyethyl, isobutyl,methoxyethyl, methyl, methylbenzyl, methylbutyl, methylsulfanylpropyl,n-butyl, n-hexyl, n-propyl, tetrahydrofurylmethyl, thiophenylmethyl andtrifluoroethyl.

When R⁴ is a ring R⁴ can be substituted with one or more substituents A,wherein A is selected from hydrogen, hydroxy, halo, nitro, oxo,C₀₋₆alkylcyano, C₀₋₄alkylC₃₋₆cycloalkyl, C₁₋₆alkyl, C₁₋₆alkylhalo,OC₁₋₆alkylhalo, C₂₋₆alkenyl, C₀₋₃alkylaryl, C₀₋₆alkylOR⁵, OC₂₋₆alkylOR⁵,C₁₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, (CO)R⁵, O(CO)R⁵, OC₂₋₆alkylcyano,OC₁₋₆alkylCO₂R⁵, O(CO)OR⁵, OC₁₋₆alkyl(CO)R⁵, C₁₋₆alkyl(CO)R⁵, NR⁵OR⁶,OC₂₋₆alkylNR⁵R⁶, C₀₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶,OC₂₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)NR⁵R⁶,O(CO)NR⁵R⁶, C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶,C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, SO₃R⁵,C₁₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)R⁵, C₀₋₆alkyl(SO₂)R⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵ and a 5-membered ring containing oneor more atoms independently selected from the group consisting of C, N,O and S.

In a preferred embodiment A is selected from hydroxy, halo, nitro, oxo,C₀₋₆alkylcyano, C₁₋₆alkyl, C₂₋₆alkenyl, C₀₋₃alkylaryl, C₀₋₆alkylOR⁵ anda 5-membered ring containing one or more atoms independently selectedfrom the group consisting of C and O.

Specific embodiments of the invention include,

-   2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   5-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-benzonitrile,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-[1,2,4]oxadiazole,-   2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-1H-benzoimidazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole,-   3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole,-   5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl-[1,2,4]oxadiazole,-   3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   3-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole,-   3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   4-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]-oxadiazole,-   2-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   3-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine,-   2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-imidazo[4,5-b]pyridine,-   5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   3-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   2-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-morpholine,-   4-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)-[1,2,4]oxadiazole,-   2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   3-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   2-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine,-   5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethoxy-phenyl)    [1,2,4]oxadiazole,-   3-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   4-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-pyridine,-   2-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-1H-imidazo[4,5-b]pyridine,-   2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H-imidazo[4,5-b],-   3-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   3-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,    or-   5-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   or salt thereof.

Further specific embodiments of the invention include,

-   4-(4-Cyclopropyl-5-{1-[5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{4-Methyl-5-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-o-tolyl-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-cyclopropyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-{3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol,-   4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   3-(4-Ethyl-5-furan-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   {3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-yl}-acetic    acid methyl ester,-   5-(2-Fluoro-5-methyl-phenyl)-3-[5-furan-2-yl-4-(2-methoxy-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(4-Cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-(5-Chloro-2-fluoro-phenyl)-5-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[3-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   3-(5-Cyclopentyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-{4-ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-4H-[1,2,4]triazol-3-ylsulfanylmethyl}-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyloxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(2-methoxy-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(4-ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-(5-{1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   5-(4-Allyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-furan-2-yl-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   {5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-methanol,-   3-(3-Chloro-phenyl)-5-[4-ethyl-5-(2-methoxy-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(4-ethyl-5-methylsulfanylmethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(5-ethoxymethyl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazole-3-carboxylic    acid methyl ester,-   2-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-(4-cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-{1-[4-ethyl-5-(tetrahydro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridazine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-ylmethyl)-pyridine,-   5-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-phenol,-   5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenoxymethyl)-4-(tetrahydro-furan-2-ylmethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-cyclopropyl-5-(4-methoxy-phenoxymethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-methoxymethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-[4-Ethyl-5-(tetrahydro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-{1-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole,-   4-{5-[3-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   3-(3-Chloro-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Methylsulfanyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-[5-(3-Methylsulfanyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,-   5-(2,5-Dimethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(2-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Cyclopropyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[2-(3-Chloro-phenyl)-oxazol-4-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-[4-Methyl-5-(5-thiophen-2-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-{4-Methyl-5-[5-(3-methylsulfanyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-Methyl-4-[3-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   1-{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenyl}-ethanone,-   4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-Methyl-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole,-   4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-(4-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(3-methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(4-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-2-methyl-pyridine,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-(5-thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-{5-[3-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[3-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole,-   3-{5-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   2-Chloro-4-[3-(4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   2-Chloro-4-[3-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   2-Chloro-4-[3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   4-[4-Methyl-5-(5-phenyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-[1,2,4]oxadiazole,-   5-(5-Bromo-2-fluoro-phenyl)-3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole,-   2-Chloro-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   4-{5-[3-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-(3-Fluoro-phenyl)-5-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-(4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   5-(5-Fluoro-2-methyl-phenyl)-3-(4-furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[3-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   3-[3-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadiazol-5-yl]-benzonitrile,-   3-[3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-Chloro-4-[3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   4-[4-Ethyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-[4-Ethyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-(4-Ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-yl-[1,2,4]triazol-4-ylamine,-   4-{5-[5-(5-Bromo-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl-[1,2,4]oxadiazole,-   3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-[1,2,4]oxadiazole,-   4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methoxy-pyridine,-   3-(3-Chloro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-Methyl-4-[3-(4-methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   4-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-pyridine,-   5-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl-[1,2,4]oxadiazole,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-[3-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-pyridine,-   3-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-benzonitrile,-   5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-{5-[5-(2,5-Dichloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(2,5-Dichloro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-propyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-propyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole,-   4-[4-Methyl-5-(3-thiophen-3-yl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   5-(4-Methyl-5-thiophen-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole,-   5-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole,-   5-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-thiophene-3-carbonitrile,-   5-(3-Chloro-phenyl)-3-[5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(5-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-pyridin-4-yl-[1,2,4]triazol-4-ylamine,-   3-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-ylamine,-   3-Pyridin-4-yl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-[1,2,4]triazol-4-ylamine,-   3-Thiophen-2-yl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-[1,2,4]triazol-4-ylamine,-   3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-pyridine,-   5-(2,5-Difluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-[4-Ethyl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-Ethyl-3-furan-2-yl-5-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazole,-   5-(3-Chloro-phenyl)-3-[5-(3,5-dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-m-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-nitro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-[5-(2,5-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(3-chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(4-chloro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole,-   3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   5-(2-Chloro-5-methyl-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole,-   3-[3-(3-Chloro-phenyl)-isoxazol-5-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   4-{5-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(2,5-Dichloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(2,5-Dichloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-4H-[1,2,4]triazole,-   4-Ethyl-3-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5-furan-2-yl-4H-[1,2,4]triazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole,-   5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-3-yl-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole,-   3-{3-[5-(3-Chloro-thiophen-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazol-5-yl}-benzonitrile,-   4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(2-fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-[3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-pyridine,-   3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole,-   5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole,-   5-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-thiophen-2-yl-[1,2,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[3-(4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazole,-   3-[5-(3-Chloro-phenyl)-oxazol-2-ylmethylsulfanyl]-4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazole,-   4-Ethyl-3-(5-thiophen-3-yl-isoxazol-3-ylmethylsulfanyl)-5-trifluoromethyl-4H-[1,2,4]triazole,-   4-{3-[5-(3-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine,-   4-{3-[5-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine,-   4-{3-[5-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine,-   4-{3-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazol-5-yl}-2-methyl-pyridine,-   4-[3-(4-Ethyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-pyridine,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole,-   4-{4-Ethyl-5-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-[5-(3,5-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[5-(2,6-difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-phenol,-   3-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   4-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-[5-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-(5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-methyl-thiazol-4-yl)-[1,2,4]oxadiazole,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-fluoro-phenyl)-[1,2,4]oxadiazole,-   4-Ethyl-3-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-5-furan-2-yl-4H-[1,2,4]triazole,-   4-(4-Ethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   4-{5-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[4-Chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-6-methyl-pyridine,-   3-[5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-Chloro-4-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-6-methoxy-pyridine,-   2-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-benzonitrile,-   5-(3-Chloro-phenyl)-3-[4-ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-5-fluoro-benzonitrile,-   4-Ethyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-2-yl-4H-[1,2,4]triazole,-   4-Methyl-3-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-5-thiophen-3-yl-4H-[1,2,4]triazole,-   4-Ethyl-3-furan-2-yl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazole,-   4-[4-Ethyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-[4-Methyl-5-(5-phenyl-isoxazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,3,4]oxadiazole,-   4-[4-Methyl-5-(5-m-tolyl-[1,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-[4-Ethyl-5-(5-m-tolyl-[1,3,4]oxadiazol-2-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   4-{5-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[3-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadiazol-5-yl]-4-fluoro-benzonitrile,-   3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-oxadiazol-5-yl]-4-fluoro-benzonitrile,-   3-[3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile,-   3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   3-[5-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-benzonitrile,-   3-[3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   5-(5-Chloro-2-fluoro-phenyl)-3-(4-methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-Chloro-4-[3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   2-Chloro-4-[3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   2-(3-Chloro-phenyl)-5-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-(4-methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-(4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazole,-   4-{4-Ethyl-5-[5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Ethyl-5-[5-(3-nitro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)-[1,3,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   3-[5-(3-Chloro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole,-   5-(3-Chloro-phenyl)-3-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[1-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-[5-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile,-   3-[5-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile,-   3-[5-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile,-   3-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-benzonitrile,-   4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-(5-Chloro-2-fluoro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-(3-Chloro-phenyl)-5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-[1-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   2-Chloro-4-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   4-{5-[5-(2-Fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Ethyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,-   2-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-ylmethylsulfanyl]-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   3-{1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4-ethyl-5-furan-2-yl-4H-[1,2,4]triazole,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-Chloro-2-[3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenol,-   2-Chloro-4-[5-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-Chloro-4-[5-(4-ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-Chloro-4-[5-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-Chloro-4-[5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-pyridine,-   2-Chloro-4-{5-[4-ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazol-2-yl}-pyridine,-   2-(3-Chloro-phenyl)-5-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(5-Bromo-2-fluoro-phenyl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,3,4]oxadiazole,-   4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(5-{1-[5-(2-Fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(4-Ethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(4-Cyclopropyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(4-Cyclopropylmethyl-5-{-[5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   2-(2-Fluoro-5-methyl-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   2-(5-Chloro-2-fluoro-phenyl)-5-[1-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazole,-   2-(5-Chloro-2-fluoro-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole,-   4-(4-Cyclopropylmethyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(4-Cyclopropyl-5-{1-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(4-Methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine,-   4-(5-{1-[4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine,-   4-{5-[1-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazol-2-yl}-2-methyl-pyridine,-   4-{5-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazol-2-yl}-2-methyl-pyridine,-   4-{5-[1-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,3,4]oxadiazol-2-yl}-2-methyl-pyridine,-   2-(3-Chloro-phenyl)-5-{1-[4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazole,-   3-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-2-methyl-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(3-Chloro-phenyl)-3-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole,-   4-(5-{1-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(5-Chloro-2-fluoro-phenyl)-3-{1-[5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,2,4]oxadiazole,-   4-[5-(4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine,-   4-[5-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-[5-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-4-cyclopropylmethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(4-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine,-   4-(5-{1-[5-(3-Fluoro-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl]-ethyl}-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine,-   3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile,-   4-Chloro-2-[3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenol,-   4-{4-Cyclopropyl-5-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Cyclopropyl-5-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Cyclopropyl-5-[5-(3-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-[4-Cyclopropyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine,-   3-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile,-   4-{4-Cyclopropyl-5-[5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-{4-Cyclopropyl-5-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethylsulfanyl]-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(4-Cyclopropyl-5-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{5-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   2-[3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-methyl-phenol,-   4-(5-{1-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   {3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenyl}-methanol,-   3-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-phenol,-   5-(3-Chloro-phenyl)-3-[4-(tetrahydro-furan-2-ylmethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   (2-Chloro-phenyl)-{5-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-isobutyl-4H-[1,2,4]triazol-3-yl}-methanol,-   5-(2-Fluoro-5-methyl-phenyl)-3-[5-thiophen-2-yl-4-(2,2,2-trifluoro-ethyl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-Furan-3-yl-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(5-furan-3-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(5-Chloro-2-fluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-thiophen-2-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-ylmethoxy}-phenol,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,3,4]oxadiazol-2-ylmethylsulfanyl]-4-ethyl-4H-[1,2,4]triazol-3-ylmethoxy}-phenol,-   3-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(2,5-Difluoro-phenyl)-5-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   4-(5-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-cyclopropyl-4H-[1,2,4]triazol-3-yl}-pyrimidine,-   2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-5-methoxy-pyrimidine,-   2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyrimidine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine,-   5-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine,-   2-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-5-methoxy-pyridine,-   3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-6-methoxy-pyridazine,-   3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-{5-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-isobutyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(3-methylsulfanyl-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-hexyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(3-fluoro-benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(3-methyl-benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(2-methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(3-methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-[4-(2-fluoro-benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yloxymethyl)-[1,2,4]oxadiazole,-   4-{5-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethoxy]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   5-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-Furan-2-yl-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzoic    acid methyl ester,-   5-(2-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(2,5-Difluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-vinyl-phenyl)-[1,2,4]oxadiazole,-   5-(3-Difluoromethoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(4-Methoxy-thiophen-3-yl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(2-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(4-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole,    -(5-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylmethyl)-[1,2,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-[2-(5-furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-[2-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,3,4]oxadiazole,-   2-(3-Chloro-phenyl)-5-[2-(4-cyclopropyl-5-furan-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,3,4]oxadiazole,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine,-   8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-thiophen-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine,-   8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine,-   5-(5-Bromo-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenylamine,-   5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-[1,2,4]oxadiazole,-   5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-[1,2,4]oxadiazole,-   2-Methyl-6-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol,-   4-(5-{2-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   8-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   8-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   8-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   8-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   3-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(1H-pyrrol-3-yl)-[1,2,4]oxadiazole,-   4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine    1-oxide,-   5-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   5-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole,-   5-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole,-   3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-hydroxy-benzonitrile,-   3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,    or-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1,1-dimethyl-ethyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   3-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethoxy}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(2-Chloro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(2,5-Difluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{1-[5-(2-Fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(4-Cyclopropyl-5-{1-[5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4H-[1,2,4]triazol-3-yl)-pyridine,-   3-{3-[1-(4-Methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazol-5-yl}-benzonitrile,-   3-{3-[1-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazol-5-yl}-benzonitrile,-   3-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethylsulfanyl}-5-pyridin-4-yl-[1,2,4]triazol-4-ylamine,-   3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   cis-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1,1-dimethyl-ethyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-methyl-ethyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-[1,3,4]oxadiazol-2-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   (S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamic    acid tert-butyl ester,-   (S)-1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine,-   (S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-dimethyl-amine,    and salts thereof.

Additional specific embodiments of the invention include:

-   4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine,-   4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{2-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{2-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(4-methyl-5-{2-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4H-1,2,4-triazol-3-yl)pyridine,-   4-(4-cyclopropyl-5-{1-methyl-2-[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4H-1,2,4-triazol-3-yl)pyridine,-   3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-ethyl}-[1,2,4]oxadiazole,-   3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole,-   4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl-1H-imidazol-2-yl)-pyridine,-   3-(3-Chloro-phenyl)-5-{2-[2-(4-methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole,-   (S)-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{(2R)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   5-(3-chlorophenyl)-3-((1R)-1-{[4-methyl-5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl]oxy}ethyl)-1,2,4-oxadiazole,-   3-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine,-   3-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   5-(3-chlorophenyl)-3-((1R)-1-{[5-(4-fluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]oxy}ethyl)-1,2,4-oxadiazole,-   5-(3-chlorophenyl)-3-((1R)-1-{[5-(3,5-difluorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]oxy}ethyl)-1,2,4-oxadiazole,-   (+)-4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   (−)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   (+)-4-(5-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   (−)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   (+)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   4-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine,-   3-Pyridin-4-yl-8-[1-(5-m-tolyl-[1,2,4]oxadiazol-3-yl)-ethyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   N,4-dimethyl-N-{[5-(3-methylphenyl)-1,2,4-oxadiazol-3-yl]methyl}-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   N-{[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   N-{[5-(4-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-N-cyclopropyl-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   (+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine,-   (−)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine,-   (+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,-   (−)-8-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine,-   (−)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   (+)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   (−)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   (+)-N-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl)[1,3,4]oxadiazol-2-yl]benzonitrile,-   3-{5-[3-(2-Methoxypyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl][1,3,4]oxadiazol-2-yl}benzonitrile,-   3-(5-{[Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amino]-methyl}[1,3,4]oxadiazol-2-yl)benzonitrile,-   3-{5-[3-(2-Methoxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile,-   3-{3-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-5-yl}benzonitrile,-   3-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl]    (methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile,-   3-(3-{[methyl(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile,-   3-(3-{[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile,-   N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-3-yl}benzonitrile,-   3-{5-[3-(2-Hydroxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile,-   N-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   N-{[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-4-cyclopropyl-N-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   [3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-ethyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   [3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-ethyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   N-{[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N-isopropyl-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   N-{1-[3-(3-Chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N-cyclopropyl-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   {1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   [5-(3-Chloro-phenyl)-isoxazol-3-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   N-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methyl}-4-cyclopropyl-N-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine,-   N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine,-   5-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)methyl]-1,2,4-oxadiazol-3-amine,-   5-(3-chlorophenyl)-N-ethyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)methyl]-1,2,4-oxadiazol-3-amine,-   Ethyl    8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate,    and salts thereof.

Further feasible examples of compounds of formula I are provided bycompounds of formula Ia

wherein:

P is selected from the group consisting of hydrogen, C₃₋₇alkyl and a 3-to 8-membered ring containing one or more atoms independently selectedfrom the group consisting of C, N, O and S, which ring may optionally befused with a 5- or 6-membered ring containing one or more atomsindependently selected from the group consisting of C, N, O and S;

R¹ is selected from the group consisting of hydrogen, hydroxy, halo,nitro, C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₁₋₆alkyl, OC₁₋₆alkyl,C₂₋₆alkenyl, OC₂₋₆alkenyl, C₂₋₆alkynyl, OC₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, OC₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,OC₀₋₆alkylaryl, CHO, (CO)R⁵, O(CO)R⁵, O(CO)OR, O(CN)OR⁵, C₁₋₆alkylOR⁵,OC₂₋₆alkylOR⁵, C₁₋₆alkyl(CO)R⁵, OC₁₋₆alkyl(CO)R⁵, C₀₋₆alkylCO₂R⁵,OC₁₋₆alkylCO₂R⁵, C₀₋₆alkylcyano, OC₂₋₆alkylcyano, C₀₋₆alkylNR⁵R⁶,OC₂₋₆alkylNR⁵R⁶, C₁₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶,C₀₋₆alkylNR⁵(CO)R⁶, OC₂₋₆alkylNR⁵ (CO)R⁶, C₀₋₆alkylNR⁵ (CO)NR⁵R⁶,C₀₋₆alkylSR⁵, OC₂₋₆alkylSR, C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵,C₀₋₆alkylSO₂R⁵, OC₂₋₆alkylSO₂R⁵, C₀₋₆alkyl(SO₂)NR⁵R⁶,OC₂₋₆alkyl(SO₂)NR⁵R⁶, C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶,C₀₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkylNR⁵(SO₂)NR⁵R⁶, (CO)NR⁵R⁶, O(CO)NR⁵R⁶,NR⁵OR⁶, C₀₋₆alkylNR⁵(CO)OR⁶, OC₂₋₆alkylNR⁵(CO)OR⁶, SO₃R⁵ and a 5- or6-membered ring containing one or more atoms independently selected fromthe group consisting of C, N, O and S, wherein said ring may besubstituted by one or more A;

M¹ is selected from the group consisting of a bond, C₁₋₃alkyl,C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl, C₀₋₃alkylOC₀₋₃alkyl,C₀₋₃alkyl(CO)NR⁵, C₀₋₃alkyl(CO)NR⁵C₀₋₃alkyl, C₀₋₄alkylNR⁵,C₀₋₃alkylSC₀₋₃alkyl, C₀₋₃alkyl(SO)C₀₋₃alkyl and C₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R² is selected from the group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,O(CO)C₁₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl,(SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ andC₀₋₄alkylNR⁵R⁶;

X¹, X² and X³ are independently selected from the group consisting ofCR, CO, N, NR, O and S;

R is selected from the group consisting of hydrogen, C₀₋₃alkyl, halo,C₀₋₃alkylOR⁵, C₀₋₃alkylNR⁵R⁶, C₀₋₃alkyl(CO)OR⁵, C₀₋₃alkylNR⁵R⁶ andC₀₋₃alkylaryl;

M² is selected from the group consisting of a bond, C₁₋₃alkyl,C₃₋₇cycloalkyl, C₂₋₃alkenyl, C₂₋₃alkynyl, C₀₋₄alkyl(CO)C₀₋₄alkyl,C₀₋₃alkylOC₀₋₃alkyl, C₀₋₃alkylNR⁵C₁₋₃alkyl, C₀₋₃alkyl(CO)NR⁵,C₀₋₄alkylNR⁵, C₀₋₃alkylSC₀₋₃alkyl, C₀₋₃alkyl(SO)C₀₋₃alkyl andC₀₋₃alkyl(SO₂)C₀₋₃alkyl;

R³ is selected from the group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,O(CO)C₁₋₄alkyl, C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl,(SO)C₀₋₄alkyl, (SO₂)C₀₋₄alkyl, OC₁₋₄alkyl, C₁₋₄alkylOR⁵ andC₀₋₄alkylNR⁵R⁶;

X⁴ is selected from the group consisting of C₀₋₄alkylR⁵,C₀₋₄alkyl(NR⁵R⁶), C₀₋₄alkyl(NR⁵R⁶)═N, NR⁵C₀₋₄alkyl(NR⁵R⁶)═N,NOC₀₋₄alkyl, C₁₋₄alkylhalo, C, O, SO, SO₂ and S;

Q is a 5- or 6-membered ring containing one or more atoms independentlyselected from C, N, O and S, which group may optionally be fused with a5- or 6-membered ring containing one or more atoms independentlyselected from C, N, O and S and which fused ring may be substituted byone or more A;

R⁴ is selected from the group consisting of hydrogen, hydroxy,C₀₋₆alkylcyano, oxo, ═NR⁵, ═NOR⁵, C₁₋₄alkylhalo, halo, C₁₋₄alkyl,OC₁₋₄alkyl, OC₀₋₆alkylaryl, O(CO)C₁₋₄alkyl, C₀₋₄alkyl(S)C₀₋₄alkyl,C₁₋₄alkyl(SO)C₀₋₄alkyl, C₁₋₄alkyl(SO₂)C₀₋₄alkyl, (SO)C₀₋₄alkyl,(SO₂)C₀₋₄alkyl, C₁₋₄alkylOR⁵, C₀₋₄alkylNR⁵R⁶ and a 5- or 6-membered ringcontaining one or more atoms independently selected from C, N, O and S,wherein said ring may be substituted by one or more A;

R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, hydroxy, C₁₋₆alkyl, C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl,C₀₋₆alkylheteroaryl and a 5- or 6-membered ring containing one or moreatoms independently selected from C, N, O and S, and wherein R⁵ and R⁶may together form a 5- or 6-membered ring containing one or more atomsindependently selected from C, N, O and S;

wherein any C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₀₋₆alkylC₃₋₆cycloalkyl, C₀₋₆alkylaryl and C₀₋₆alkylheteroaryl definedunder R¹, R², R³R⁴, R⁵ and R⁶ may be substituted by one or more A; and

A is selected from the group consisting of hydrogen, hydroxy, oxo, halo,nitro, C₀₋₆alkylcyano, C₁₋₄alkyl, C₀₋₄alkylC₃₋₆cycloalkyl,C₁₋₆alkylhalo, OC₁₋₆alkylhalo, C₂₋₆alkenyl, OC₁₋₆alkyl, C₀₋₃alkylaryl,C₀₋₆alkylOR⁵, OC₂₋₆alkylOR⁵, C₁₋₆alkylSR⁵, OC₂₋₆alkylSR⁵, (CO)R⁵,O(CO)R⁵, OC₂₋₆alkylcyano, C₀₋₆alkylCO₂R⁵, OC₁₋₆alkylCO₂R⁵, O(CO)OR⁵,OC₁₋₆alkyl(CO)R⁵, C₁₋₆alkyl(CO)R⁵, NR⁵OR⁶, C₀₋₆alkylNR⁵R⁶,OC₂₋₆alkylNR⁵R⁶, C₀₋₆alkyl(CO)NR⁵R⁶, OC₁₋₆alkyl(CO)NR⁵R⁶,OC₂₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)R⁶, C₀₋₆alkylNR⁵(CO)NR⁵R⁶,O(CO)NR⁵R⁶, NR⁵(CO)OR⁶, C₀₋₆alkyl(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)NR⁵R⁶,C₀₋₆alkylNR⁵(SO₂)R⁶, OC₂₋₆alkylNR⁵(SO₂)R⁶, SO₃R⁵,C₁₋₆alkylNR⁵(SO₂)NR⁵R⁶, OC₂₋₆alkyl(SO₂)R⁵, C₀₋₆alkyl(SO₂)R⁵,C₀₋₆alkyl(SO)R⁵, OC₂₋₆alkyl(SO)R⁵ and a 5- or 6-membered ring containingone or more atoms independently selected from C, N, O and S;

m is selected from 0, 1, 2, 3 and 4; and

n is selected from 0, 1, 2 and 3,

or salt thereof.

The present invention relates to the use of compounds of formula I andIA as hereinbefore defined as well as to the salts thereof. Salts foruse in pharmaceutical formulations will be pharmaceutically acceptablesalts, but other salts may be useful in the production of the compoundsof formula I and Ia.

Examples of pharmaceutically acceptable salts may be, but are notlimited to hydrochloride, 4-aminobenzoate, anthranilate,4-aminosalicylate, 4-hydroxybenzoate, 3,4-dihydroxybenzoate,3-hydroxy-2-naphthoate, nitrate and trifluoroacetate. Otherpharmaceutically acceptable salts and methods of preparing these saltsmay be found in, for example, Remington's Pharmaceutical Sciences(18^(th) Edition, Mack Publishing Co.).

Some compounds of formula I may have chiral centres and/or geometricisomeric centres (E- and Z-isomers), and it is to be understood that theinvention encompasses all such optical, diastereoisomers and geometricisomers.

The invention relates to any and all tautomeric forms of the compoundsof formula I.

The invention relates to the following compounds, which may be used asintermediates in the preparation of a compound of formula I;

-   6-Methylpyridine-4-carboxylic acid,-   1-Cyano-3-ethylbenzene,-   3-Ethylbenzoic acid,-   3-Fluoro-5-methyl-benzoic acid,-   3-Methoxymethyl-benzoic acid,-   N-Hydroxy-3-methoxy-benzamidine,-   N-Hydroxy-benzamidine,-   N-Hydroxy-3-methyl-benzamidine,-   5-Chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole,-   5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole,-   5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile,-   3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile,-   3-Chloromethyl-5-m-tolyl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine,-   3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole,-   4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine,-   3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine,-   3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole,-   5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole,-   5-Furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol,-   4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol,-   4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol,-   5-(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol,-   4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol,-   4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol,-   4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol,-   5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-Chloro-thiophene-3-carboxylic acid,-   3-Methylsulfanyl-benzoic acid,-   3-Cyclopropyl-benzoic acid,-   3-tert-Butoxycarbonylamino-benzoic acid,-   3-Acetyl-benzoic acid,-   2-Methyl-isonicotinic acid hydrazide,-   5-Chloro-2-fluoro-benzoic acid hydrazide,-   3-Cyano-benzoic acid hydrazide,-   2-Chloro-isonicotinic acid hydrazide,-   2-Fluoro-5-methyl-benzoic acid hydrazide,-   Pyrimidine-4-carboxylic acid hydrazide,-   3-Fluoro-N-hydroxy-benzamidine,-   N-Hydroxy-thiophene-3-carboxamidine,-   2-Chloro-N-hydroxy-propionamidine,-   3,N-Dihydroxy-benzamidine,-   N-Hydroxy-2-methyl-benzamidine,-   N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine,-   3-Chloro-N-hydroxy-benzamidine,-   N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine,-   2,5-Difluoro-N-hydroxy-benzamidine,-   4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol,-   4-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   5-Thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol,-   5-(2-Fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,-   5-(2-Chloro-6-methyl-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(tetrahydro-furan-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acid    methyl ester,-   5-(2-Chloro-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(2-Chloro-6-methoxy-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol,-   4-Propyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol,-   3-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-benzonitrile,-   5-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole-3-thiol,-   5-(3,5-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(2,6-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-pyrimidin-5-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-furan-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-(Tetrahydrofuran-2-ylmethyl)-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-Cyclopentyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-(3,5-Dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(3-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-(3-nitrophenyl)-4H-[1,2,4]triazole-3-thiol,-   5-(2,5-Difluorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(3-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   5-(4-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Allyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(4-methoxy-phenoxymethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-phenoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-hydroxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-methylsulfanylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-Ethoxymethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-Furan-3-yl-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Methyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-pyridazin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-pyridin-4-ylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(6-hydroxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(4-hydroxy-phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-p-tolyloxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(2-methoxy-pyridin-4-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(5-methoxy-pyrimidin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol,-   4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,-   4-Cyclopropylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol,-   4-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-Furan-2-yl-4-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Cyclopropyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   (3-Thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic    acid methyl ester,-   4-Cyclopropylmethyl-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-(2-Methoxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   Thiophen-2-yl-4-(2,2,2-trifluoroethyl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Cyclopropyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Cyclopropyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol,-   4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole,-   4-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   4-(2-Hydroxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine,-   Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine,-   3-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   3-Furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine,-   4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione,-   5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole,-   5-Chloromethyl-3-(3-fluoro-phenyl)-[1,2,4]oxadiazole,-   5-Chloromethyl-3-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   5-Chloromethyl-3-thiophen-2-yl-[1,2,4]oxadiazole,-   5-Chloromethyl-3-thiophen-3-yl-[1,2,4]oxadiazole,-   3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-phenol,-   5-Chloromethyl-3-o-tolyl-[1,2,4]oxadiazole,-   5-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile,-   2-Chloro-4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-pyridine,-   3-Chloromethyl-5-(2,5-dimethyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2,5-dichloro-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2-fluoro-5-bromo-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-methyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-methylsulfanyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(3-cyclopropyl-phenyl)-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic acid    tert-butyl ester,-   1-[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-ethanone,-   5-(5-Chloro-2-fluoro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole,-   2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-phenol,-   3-Chloromethyl-5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2,5-dichloro-thiophen-3-yl)-[1,2,4]oxadiazole,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile,-   3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(2-methyl-thiazol-4-yl)-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(4-fluoro-phenyl)-[1,2,4]oxadiazole,-   5-(5-Bromo-2-fluoro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(4-methyl-thiophen-2-yl)-[1,2,4]oxadiazole,-   5-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-thiophene-3-carbonitrile,-   2-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-benzonitrile,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-fluoro-benzonitrile,-   3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro-benzonitrile,-   4-Chloro-2-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenol,-   3-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   3-(1-Chloro-ethyl)-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole,-   3-(1-Chloro-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazole,-   [3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol,-   3-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-[1,2,4]oxadiazole,-   3-Chloromethyl-5-furan-3-yl-[1,2,4]oxadiazole,-   3-Chloromethyl-5-(5-chloro-thiophen-2-yl)-[1,2,4]oxadiazole,-   1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol,-   [5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol,-   1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol,-   [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol,-   2-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,-   2-Chloromethyl-5-(3-chloro-phenyl)-[1,3,4]oxadiazole,-   4-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-2-methyl-pyridine,-   2-Chloromethyl-5-m-tolyl-[1,3,4]oxadiazole,-   3-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-benzonitrile,-   2-Chloro-4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)-pyridine,-   2-(5-Chloro-2-fluoro-phenyl)-5-chloromethyl-[1,3,4]oxadiazole,-   2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole,-   2-(1-Bromo-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[1,3,4]oxadiazole,-   4-[5-(1-Bromo-ethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl-pyridine,-   2-(1-Bromo-ethyl)-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole,-   2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole,-   3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole,-   1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol,-   1-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethanol,-   5-(2-Fluoro-5-methyl-phenyl)-isoxazole-3-carboxylic acid methyl    ester,-   5-Thiophen-3-yl-isoxazole-3-carboxylic acid methyl ester,-   5-Phenyl-isoxazole-3-carboxylic acid methyl ester,-   5-(3-Chloro-phenyl)-4-methyl-isoxazole-3-carboxylic acid ethyl    ester,-   5-(5-Chloro-thiophen-3-yl)-isoxazole-3-carboxylic acid methyl ester,-   [5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol,-   [2-(3-Chloro-phenyl)-oxazol-4-yl]-methanol,-   [3-(3-Chloro-phenyl)-isoxazol-5-yl]-methanol,-   5-(Thiophen-3-yl-isoxazol-3-yl)methanol,-   [5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-methanol,-   (5-Phenyl-isoxazol-3-yl)-methanol,-   [5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-yl]-methanol,-   [5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yl)]-methanol,-   Methanesulfonic acid 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl    ester,-   Methanesulfonic acid 2-(3-chloro-phenyl)-oxazol-4-ylmethyl ester,-   Methanesulfonic acid 3-(3-chloro-phenyl)-isoxazol-5-ylmethyl ester,-   Methanesulfonic acid    5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid-phenyl)-isoxazol-5-yl]-ethyl ester,-   Methanesulfonic acid    5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid    5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid    5-(3-chloro-phenyl)-4-methyl-isoxazol-3-ylmethyl ester,-   Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-3-ylmethyl    ester,-   Methanesulfonic acid    1-[5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethyl ester,-   Methanesulfonic acid    1-[5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethyl ester,-   Methanesulfonic acid    4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester,-   Pyrimidine-4-carboxylic acid,-   3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester,-   2-Bromomethyl-5-(3-chloro-phenyl)-oxazole,-   2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester,-   2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester,-   1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol,-   1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol,-   [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol,-   3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid    hydrazide,-   3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid    hydrazide,-   3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid    ethyl ester hydrochloride,-   3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid    hydrazide,-   [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide,-   (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid    hydrazide,-   3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-butyric acid    hydrazide,-   3-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one,-   3-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one,-   3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole,-   1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole,-   (4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetonitrile,-   2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic    acid,-   2-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic    acid,-   3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole    or,-   {3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl-phenyl}-carbamic    acid tert-butyl ester.    Pharmaceutical Formulations

According to one aspect of the present invention there is provided apharmaceutical formulation comprising a compound of formula I, or saltthereof, for use in the prevention and/or treatment of metabotropicglutamate receptor subtype 5 receptor (mGluR5) mediated disorders andany disorder listed below.

The composition may be in a form suitable for oral administration, forexample as a tablet, pill, syrup, powder, granule or capsule, forparenteral injection (including intravenous, subcutaneous,intramuscular, intravascular or infusion) as a sterile solution,suspension or emulsion, for topical administration as an ointment, patchor cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using one or more conventional excipients, pharmaceuticaldiluents and/or inert carriers.

According to another aspect of the invention there is provided apharmaceutical formulation comprising as active ingredient atherapeutically effective amount of a compound of formula I inassociation with one or more pharmaceutically acceptable diluent,excipients and/or inert carrier.

Suitable daily doses of the compounds of formula I in the treatment of amammal, including man are approximately 0.01 to 250 mg/kg bodyweight atperoral administration and about 0.001 to 250 mg/kg bodyweight atparenteral administration. The typical daily dose of the activeingredients varies within a wide range and will depend on variousfactors such as the relevant indication, the route of administration,the age, weight and sex of the patient and may be determined by aphysician.

Medical Use

It has been found that the compounds according to the present invention,or salts thereof, exhibit a high degree of potency and selectivity forindividual metabotropic glutamate receptor (mGluR) subtypes. Inparticular there are compounds according to the present invention thatare potent and selective for the mGluR Group I receptor and moreparticularly for mGluR5. Accordingly, the compounds of the presentinvention are expected to be useful in the prevention and/or treatmentof conditions associated with excitatory activation of an mGluR Group Ireceptor and for inhibiting neuronal damage caused by excitatoryactivation of an mGluR Group I receptor, specifically when the mGluRGroup I receptor is mGluR5. The compounds may be used to produce aninhibitory effect of mGluR Group I, especially mGluR5, in mammals,including man.

mGluR5 is highly expressed in the central and peripheral nervous systemand in other tissues. Thus, it is expected that the compounds of theinvention are well suited for the prevention and/or treatment of mGluR5receptor-mediated disorders such as acute and chronic neurological andpsychiatric disorders and chronic and acute pain disorders.

Further disorders are Alzheimer's disease, senile dementia, AIDS-induceddementia, Parkinson's disease, amyotrophic lateral sclerosis,Huntington's Chorea, migraine, epilepsy, schizophrenia, depression,anxiety, acute anxiety, obsessive compulsive disorder, opthalmologicaldisorders such as retinopathies, diabetic retinopathies, glaucoma,auditory neuropathic disorders such as tinnitus, chemotherapy inducedneuropathies, post-herpetic neuralgia and trigeminal neuralgia,tolerance, dependency, addiction and craving disorders,neurodevelopmental disorders including Fragile X, autism, mentalretardation, schizophrenia and Down's Syndrome.

The compounds are also well suited for the prevention and/or treatmentof pain related to migraine, inflammatory pain, neuropathic paindisorders such as diabetic neuropathies, arthritis and rheumatitioddiseases, low back pain, post-operative pain and pain associated withvarious conditions including angina, renal or billiary colic,menstruation, migraine and gout.

Other disorders are stroke, head trauma, anoxic and ischemic injuries,hypoglycemia, cardiovascular diseases and epilepsy.

The dose required for the therapeutic or preventive treatment of aparticular disorder will necessarily be varied depending on the hosttreated, the route of administration and the severity of the illnessbeing treated.

The invention relates to compounds of formula I as defined hereinbefore,for use in therapy.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of neurological disorders.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of psychiatric disorders.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of chronic and acute paindisorders.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of mGluR5 receptor-mediateddisorders.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of Alzheimer's disease seniledementia, AIDS-induced dementia, Parkinson's disease, amylotropiclateral sclerosis, Huntington's Chorea, migraine, epilepsy,schizophrenia, depression, anxiety, acute anxiety, opthalmologicaldisorders such as retinopathies, diabetic retinopathies, glaucoma,auditory neuropathic disorders such as tinnitus, chemotherapy inducedneuropathies, post-herpetic neuralgia and trigeminal neuralgia,tolerance, dependency, Fragile X, autism, mental retardation,schizophrenia and Down's Syndrome.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of pain related to migraine,inflammatory pain, neuropathic pain disorders such as diabeticneuropathies, arthritis and rheumatitiod diseases, low back pain,post-operative pain and pain associated with various conditionsincluding angina, renal or billiary colic, menstruation, migraine andgout.

The invention relates to compounds of formula I as defined hereinbefore,for use in prevention and/or treatment of stroke, head trauma, anoxicand ischemic injuries, hypoglycemia, cardiovascular diseases andepilepsy.

The present invention relates to the use of a compound according toFormula I and Formula II in the treatment of gastrointestinal disorders.

Another embodiment of the invention relates to the use of a compoundaccording to Formula I and Formula II, for the manufacture of amedicament for the inhibition of transient lower esophageal sphincterrelaxations, for the treatment of GERD, for the prevention of G.I.reflux, for the treatment regurgitation, treatment of asthma, treatmentof laryngitis, treatment of lung disease and for the management offailure to thrive.

The present invention relates also to the use of a compound of formula Ias defined hereinbefore, in the manufacture of a medicament for theprevention and/or treatment of mGluR5 receptor-mediated disorders andany disorder listed above.

The invention also provides a method of treatment and/or prevention ofmGluR5 receptor-mediated disorders and any disorder listed above, in apatient suffering from, or at risk of, said condition, which comprisesadministering to the patient an effective amount of a compound offormula I, as hereinbefore defined.

In the context of the present specification, the term “therapy” includestreatment as well as prevention, unless there are specific indicationsto the contrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

In this specification, unless stated otherwise, the term ‘antagonist’means a compound that by any means, partly or completely, blocks thetransduction pathway leading to the production of a response by theligand.

The term “disorder”, unless stated otherwise, means any condition anddisease associated with metabotropic glutamate receptor activity.

Non-Medical Use

In addition to their use in therapeutic medicine, the compounds offormula I or salt thereof, are also useful as pharmacological tools inthe development and standardisation of in vitro and in vivo test systemsfor the evaluation of the effects of inhibitors of mGluR relatedactivity in laboratory animals such as cats, dogs, rabbits, monkeys,rats and mice, as part of the search for new therapeutics agents.

Pharmacology

The pharmacological properties of the compounds of the invention can beanalyzed using standard assays for functional activity. Examples ofglutamate receptor assays are well known in the art as described in forexample Aramori et al., Neuron 8:757 (1992), Tanabe et al., Neuron 8:169(1992), Miller et al., J. Neuroscience 15: 6103 (1995), Balazs, et al.,J. Neurochemistry 69:151 (1997). The methodology described in thesepublications is incorporated herein by reference. Conveniently, thecompounds of the invention can be studied by means of an assay thatmeasures the mobilization of intracellular calcium, [Ca²⁺]_(i) in cellsexpressing mGluR5.

Intracellular calcium mobilization was measured by detecting changes influorescence of cells loaded with the fluorescent indicator fluo-3.Fluorescent signals were measured using the FLIPR system (MolecularDevices). A two addition experiment was used that could detect compoundsthat either activate or antagonize the receptor.

For FLIPR analysis, cells expressing human mGluR5d were seeded oncollagen coated clear bottom 96-well plates with black sides andanalysis of [Ca²⁺]_(i) mobilization was done 24 hours after seeding.

FLIPR experiments were done using a laser setting of 0.800 W and a 0.4second CCD camera shutter speed. Each FLIPR experiment was initiatedwith 160 μL of buffer present in each well of the cell plate. After eachaddition of the compound, the fluorescence signal was sampled 50 timesat 1 second intervals followed by 3 samples at 5 second intervals.Responses were measured as the peak height of the response within thesample period.

EC₅₀ and IC₅₀ determinations were made from data obtained from 8-pointconcentration response curves (CRC) performed in duplicate. Agonist CRCwere generated by scaling all responses to the maximal response observedfor the plate. Antagonist block of the agonist challenge was normalizedto the average response of the agonist challenge in 14 control wells onthe same plate.

We have validated a secondary functional assay for mGluR5d based onInositol Phosphate (IP₃) turnover. IP₃ accumulation is measured as anindex of receptor mediated phospholipase C turnover. GHEK cells stablyexpressing the human mGluR5d receptors were incubated with [3H]myo-inositol overnight, washed three times in HEPES buffered saline andpre-incubated for 10 minutes with 10 mM LiCl. Compounds (agonists) wereadded and incubated for 30 minutes at 37° C. Antagonist activity wasdetermined by pre-incubating test compounds for 15 minutes, thenincubating in the presence of glutamate (80 μM) or DHPG (30 μM) for 30minutes. Reactions were terminated by the addition of perchloric acid(5%). Samples were collected and neutralized, and inositol phosphateswere separated using Gravity-Fed Ion-Exchange Columns.

A detailed protocol for testing the compounds of the invention isprovided below in Pharmaceutical Examples.

Abbreviations

FLIPR Fluorometric Imaging Plate reader

CCD Charge Coupled Device

CRC Concentration Response Curve

GHEK Human Embrionic Kidney expressing Glutamate Transporter

HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (buffer)

IP₃ inositol triphosphate

DHPG 3,5-dihydroxyphenylglycine;

BSA Bovine Serum Albumin

EDTA Ethylene Diamine Tetraacetic Acid

Methods of Preparation

Another aspect of the present invention provides a process for preparinga compound of formula I, or salt thereof.

Throughout the following description of such processes it is understoodthat, where appropriate, suitable protecting groups will be added to,and subsequently removed from, the various reactants and intermediatesin a manner that will be readily understood by one skilled in the art oforganic synthesis. Conventional procedures for using such protectinggroups as well as examples of suitable protecting groups are described,for example, in “Protective Groups in Organic Synthesis” T. W. Green, P.G. M. Wuts, Wiley-Interscience, New York, 1999. It is also to beunderstood that a transformation of a group or substituent into anothergroup or substituent by chemical manipulation can be conducted on anyintermediate or final product on the synthetic path toward the finalproduct, in which the possible type of transformation is limited only byinherent incompatibility of other functionalities carried by themolecule at that stage to the conditions or reagents employed in thetransformation. Such inherent incompatibilities, and ways to circumventthem by carrying out appropriate transformations and synthetic steps ina suitable order, will be readily understood to the one skilled in theart of organic synthesis. Examples of transformations are given below,and it is to be understood that the described transformations are notlimited only to the generic groups or substituents for which thetransformations are exemplified. References and descriptions on othersuitable transformations are given in “Comprehensive OrganicTransformations—A Guide to Functional Group Preparations” R. C. Larock,VHC Publishers, Inc. (1989). References and descriptions of othersuitable reactions are described in textbooks of organic chemistry, forexample, “Advanced Organic Chemistry”, March, 4^(th) ed. McGraw Hill(1992) or, “Organic Synthesis”, Smith, McGraw Hill, (1994). Techniquesfor purification of intermediates and final products include forexample, straight and reversed phase chromatography on column orrotating plate, recrystallisation, distillation and liquid-liquid orsolid-liquid extraction, which will be readily understood by the oneskilled in the art. The definitions of substituents and groups are as informula I except where defined differently. The term “room temperature”and “ambient temperature” shall mean, unless otherwise specified, atemperature between 16 and 25° C.

Unless specified otherwise, are P, Q, X¹, X², X³, X⁴, R, R¹, R², R³, R⁴,R⁵R⁶, M¹, M², m and n, defined as in formula I.

All starting materials are commercially available or earlier describedin the literature.

The ¹H and ¹³C NMR spectra were recorded either on Bruker 300, BrukerDPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHzfor ¹H NMR respectively, using TMS or the residual solvent signal asreference, in deuterated chloroform as solvent unless otherwiseindicated. All reported chemical shifts are in ppm on the delta-scale,and the fine splitting of the signals as appearing in the recordings (s:singlet, d: doublet, t: triplet, q: quartet, m: multiplet).

Analytical in line liquid chromatography separations followed by massspectra detections, were recorded on a Waters LCMS consisting of anAlliance 2795 (LC) and a ZQ single quadropole mass spectrometer. Themass spectrometer was equipped with an electrospray ion source operatedin a positive or negative ion mode. The ion spray voltage was ±3 kV andthe mass spectrometer was scanned from m/z 100-700 at a scan time of 0.8s. To the column, X-Terra MS, Waters, C8, 2.1×50 mm, 3.5 μm, was applieda linear gradient from 5% to 100% acetonitrile in 10 mM ammonium acetate(aq.), or in 0.1% TFA (aq.).

Preparative reversed phase chromatography was run on a Gilsonautopreparative HPLC with a diode array detector using an XTerra MS C8,19×300 mm, 7 μm as column.

MS-triggered preparative reversed phase chromatograpy was run on aWaters autopurification LC-MS system with a diode array detector and aZQ mass detector using an XTerra MS C8, 19×100 mm, 5 μm as column.

Purification by a chromatotron was performed on rotating silicagel/gypsum (Merck, 60 PF-254 with calcium sulphate) coated glass sheets,with coating layer of 1, 2, or 4 mm using a TC Research 7924Tchromatotron.

Purification of products were also done using Chem Elut ExtractionColumns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPEColumns (Varian, cat #12256018; 12256026; 12256034), or by flashchromatography in silica-filled glass columns.

Microwave heating was performed in a Smith Synthesizer Single-modemicrowave cavity producing continuous irradiation at 2450 MHz (PersonalChemistry AB, Uppsala, Sweden).

Abbreviations:

-   -   atm atmosphere    -   aq. aqueous    -   CDI N,N′-Carbonyldiimidazole    -   d day(s)    -   DBU 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DCC N,N-Dicyclohexylcarbodiimide    -   DCM Dichloromethane    -   DEA N,N-Diisopropyl ethylamine    -   DIC N,N′-Diisopropylcarbodiimide    -   DMAP N,N-Dimethyl-4-aminopyridine    -   DMF N,N-dimethylformamide    -   DMSO Dimethylsulfoxide    -   EA Ethyl acetate    -   BOPA Benzoyl Peroxide    -   EDCl N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide        hydrochloride    -   EtOH Ethanol    -   Et₂O Diethylether    -   h hour(s)    -   hep heptane    -   hex hexane(s)    -   P-BEMP Polystyrene bound        2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine    -   Deoxofluor [Bis(2-methoxyethyl)amino]sulfur trifluoride    -   DAST (Diethylamino)sulfur trifluoride    -   EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   HOBt 1-hydroxybenzotriazole hydrate    -   THF tetrahydrofuran    -   TFA trifluoroacetic acid    -   Et ethyl    -   Ac acetyl    -   DIBAL diisobutylaluminum hydride    -   M, N molar and normal    -   MeOH Methanol    -   HBTU O-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium        hexafluorophosphate    -   Boc tert-butoxycarbonyloxy    -   HMDS hexamethyl disilazide    -   Ms mesylate or methanesulphonyl    -   min minutes    -   NADPH Nicotinamide-adenine dinucleotide phosphate, reduced    -   nBuLi 1-butyl lithium    -   NBS N-bromosuccinimid    -   Novozyme 435® Trademark name for polymer supported Candida        Antartica Lipase    -   o.n. over night    -   prep preparative    -   r.t. or rt room temperature    -   sat. saturated    -   TEA Triethylamine    -   LDA Lithium diisopropylamine    -   LHA Lithium aluminium hydride    -   MCPBA meta-chloroperoxybenzoic acid    -   SPE solid phase extraction    -   Lawesson's Reagent        [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide    -   TFA Trifluoroacetic acid    -   Ts tosyl or para-toluene sulphonyl

General Syntheses of Compounds of Formula V.

A compound of formula V, wherein R⁷ is independently selected from agroup consisting of M¹-(R²)_(n)—P—(R¹)_(m1), M²-(R³)_(n)—X⁴-Q-(R⁴)_(m2),and M²-(R³)_(n)-G wherein G is a leaving group or a group which maysubsequently be transformed into a leaving group, may be preparedthrough cyclization of a compound of formula IV formed from a suitablyactivated compound of formula III, wherein LG is a leaving group, with acompound of formula II. The compound of formula II may be prepared froma suitable nitrile by addition of hydroxylamine in a suitable solventsuch as, methanol, ethanol, water or mixture thereof, using anappropriate base such as hydroxide, carbonate or acetate.

The compound of formula III may be activated as follows; i) as the acidchloride formed from the acid using a suitable reagent such as oxalylchloride or thionyl chloride; ii) as an anhydride or mixed anhydrideformed from treatment with a reagent such as alkyl chloroformate; iii)using traditional methods to activate acids in amide coupling reactionssuch as EDCI with HOBt or uronium salts like HBTU; iv) as an alkyl esterwhen the hydroxyamidine is deprotonated using a strong base liketert-butoxide; v) by any other suitable method of activation for thedesired substrate.

The ester formation may be accomplished using an appropriate aproticsolvent such as dichloromethane, tetrahydrofuran, N,N-dimethylformamideor toluene, with optionally an appropriate organic base such astriethylamine, diisopropylethylamine and the like or an inorganic basesuch sodium bicarbonate or potassium carbonate.

The cyclization of the ester to form an oxadiazole may be carried out onthe crude ester, with evaporation and replacement of the solvent with ahigher boiling solvent such as DMF, or with aqueous extraction toprovide a semi-purified material or with material purified by standardchromatographic methods. The cyclization may be accomplished by heatingconventionally or by microwave irradiation (100-180° C.), in a suitablesolvent such as pyridine or N,N-dimethylformamide or using a lowertemperature method employing reagents like tetrabutylammonium fluoridein tetrahydrofuran or by any other suitable known literature method.

Other compatible non-reacting functional groups suitably protected mayalso be present in the substrates.

Further examples of the above described reactions can be found inPoulain et al., Tetrahedron Lett., (2001), 42, 1495-98, Ganglott et al.,Tetrahedron Lett., (2001), 42, 1441-43, which are hereby included asreferences.

Synthesis of Nitriles and Acids for Use in Preparation of Compounds ofFormula II and III

Aryl nitrites are available by a variety of methods including cyanationof an aryl halide or triflate under palladium or nickel catalysis usingan appropriate cyanide source such as zinc cyanide in an appropriatesolvent such as N,N-dimethylformamide. The corresponding acid isavailable from the nitrile by hydrolysis under either acidic or basicconditions in an appropriate solvent such as aqueous alcohols. Arylacids are also available from a variety of other sources, includingiodo- or bromo-lithium exchange followed by trapping with CO₂ to givedirectly the acid.

The acid may be converted to the primary amide using any compatiblemethod to activate the acid, including via the acid chloride or mixedanhydride, followed by trapping with any source of ammonia, includingammonium chloride in the presence of a suitable base, ammoniumhydroxide, methanolic ammonia or ammonia in an aprotic solvent such asdioxane. This amide intermediate may be converted to the nitrile using avariety of dehydration reagents such as oxalyl chloride or thionylchloride. This reaction sequence to convert an acid into a nitrile mayalso be applied to non-aromatic acids, including suitably protectedamino acid derivatives. A suitable protecting group for an amine, in anamino acid or in a remote position of any other acid starting material,may be any group which removes the basicity and nucleophilicity of theamine functionality, including such carbamate protecting group as Boc.

Some acids are more easily prepared taking advantage of commerciallyavailable analogs. For example, 6-methylpyridine-4-carboxylic acid isprepared by dechlorination of 2-chloro-6-methylpyridine-4-carboxylicacid. Certain types of substituted fluoro-benzonitriles and benzoicacids are available from bromo-difluoro-benzene via displacement of onefluoro group with a suitable nucleophile such as imidazole in thepresence of a base such as potassium carbonate in a compatible solventsuch as N,N-dimethylformamide at elevated temperatures (80-120° C.) forextended periods of time. The bromo group may subsequently be elaboratedinto the acid or nitrile as above.

1,3-Disubstituted and 1,3,5-trisubstituted benzoic acids andbenzonitriles may be prepared by taking advantage of readily availablesubstituted isophthalic acid derivatives. Monohydrolysis of the diesterallows selective reaction of the acid with a variety of reagents, mosttypically activating agents such as thionyl chloride, oxalyl chloride orisobutyl chloroformate and the like. From the activated acid, a numberof products are available. In addition to the primary amide used to formthe nitrite by dehydration as mentioned above, reduction to thehydroxymethyl analog may be carried out on the mixed anhydride or acidchloride using a variety of reducing agents such as sodium borohydridein a compatible solvent such as tetrahydrofuran. The hydroxymethylderivative may be further reduced to the methyl analog using catalytichydrogenation with an appropriate source of catalyst such as palladiumon carbon in an appropriate solvent such as ethanol. The hydroxymethylgroup may also be used in any reaction suitable for benzylic alcoholssuch as acylation, alkylation, transformation to halogen and the like.Halomethylbenzoic acids of this type may also be obtained frombromination of the methyl derivative when not commercially available.Ethers obtained by alkylation of the hydroxymethyl derivatives may alsobe obtained from the halomethylaryl benzoate derivatives by reactionwith the appropriate alcohol using an appropriate base such as potassiumcarbonate or sodium hydroxide in an appropriate solvent such astetrahydrofuran or the alcohol. When other substituents are present,these may also be employed in standard transformation reactions.Treatment of an aniline with acid and sodium nitrite may yield adiazonium salt, which may be transformed into a halide such as fluorideusing tetrafluoroboric acid. Phenols react in the presence of a suitablebase such as potassium carbonate with alkylating agents to form aromaticethers.

Formation of Compounds of Formula IX

A compound of formula IX, wherein R⁷ is independently selected from agroup consisting of M¹-(R²)_(n)—P—(R¹)_(m1), M²-(R³)_(n)—X⁴-Q-(R⁴)_(m2),and M²-(R³)_(n)-G wherein G is a leaving group or a group which maysubsequently be transformed into a leaving group, may be prepared by a1,3-dipolar cycloaddition between compounds of formula VI and VII underbasic conditions using a suitable base such as sodium bicarbonate ortriethylamine at suitable temperatures (0° C.-100° C.) in solvents suchas toluene. Synthesis of compounds of type VI has previously beendescribed in the literature, e.g. Kim, Jae Nyoung; Ryu, Eung K; J. Org.Chem. (1992), 57, 6649-50. 1,3-Dipolar cycloaddition with acetylenes oftype VII can also be effected using substituted nitromethanes of typeVIII via activation with an electrophilic reagent such as PhNCO in thepresence of a base such as triethylamine at elevated temperatures(50-100° C.). Li, C-S.; Lacasse, E.; Tetrahedron Lett. (2002) 43;3565-3568. Several compounds of type VII are commercially available, ormay be synthesized by standard methods as known by one skilled in theart.

Alternatively, compounds of formula X, which are available from aClaisen condensation of a methyl keone and an ester using basicconditions using such bases as sodium hydride or potassiumtert-butoxide, may yield compounds of formula IX via condensation andsubsequent cyclization using hydroxylamine, for example in the form ofthe hydrochloric acid salt, at elevated temperatures (60-120° C.).

It is understood that for both methods subsequent functional grouptransformations may be necessary. In the case of an ester group, thesetransformations may include, but is not limited to either of followingthree procedures: a) Complete reduction using a suitable reducing agentsuch as LAH in solvents such as THF. b) Partial reduction using asuitable selective reducing agent such as DIBAL followed by alkylationwith an alkylhalide. c) Alkylation using an alkylmetal reagent such asan alkyl magnesium halide in solvents such as toluene or THF, followedby reduction with for example sodium borohydride in methanol.

Formation of Compounds of Formula XIV

A compound of formula XIV, wherein R⁷ is independently selected from agroup consisting of M¹-(R²)_(n)—P—(R¹)_(m1), M²-(R³)_(n)—X⁴-Q-(R⁴)_(m2),and M²-(R³)_(n)-G wherein G is a leaving group or a group which maysubsequently be transformed into a leaving group, may be prepared fromtetrazole compounds of type XI via acylation using an isolable compoundof type III such as an acid chloride or anhydride, or a compound of typeIII wherein the LG may be formed in situ, for example from activation ofan acid using a reagent such as DCC or EDCI, followed by rearrangementto the 1,3,4-oxadizaole. Jursic, B. S.; Zdravkovski, Z.; Synth. Commun.;(1994) 24; 1575-1582.

Alternatively, compounds of formula XIV may also be prepared from acylhydrazide of type XII via heating in the presence of compounds offormula XIII or III, wherein LG is a leaving group such as chloride oralkoxide, at elevated temperatures (60-130° C.) in one step. Thereaction of compounds of Formula XIII may be carried out neat or using asuitable aprotic solvent such as benzene or xylene, or a protic solventsuch as ethanol or n-butanol, and may be facilitated by the presence ofabase such as KOtBu or a acid such as p-toluene sulfonic acid or aceticacid. Se references: Saunders, J.; Cassidy, M.; Freedman, S. B.; Harley,E. A.; Iversen, L. L. J. Med. Chem.; (1990) 33; 1128-1138; Peet, N. P.;Sunder, S. J. Heterocycl. Chem.; (1984) 21; 1807-1816. For compounds offormula III a dehydrating agent such as phosphorous pentoxide may beused to increase cyclization of the formed reaction intermediate as hasbeen previously been described for example by Kakefuda, Akio; et al.;Bioorg. Med. Chem. (2002), 10; 1905-1912.

Formation of Compounds of Formula XVI

A compound of formula XVI, wherein R⁸ as defined above is independentlyselected from a group consisting of M¹-(R²)_(n)—P—(R¹)_(m1),M²-(R³)_(n)—X⁴-Q-(R⁴)_(m2), and M²-(R³)_(n)-G wherein G is a leavinggroup or a group which may subsequently be transformed into a leavinggroup, may be prepared by the reaction of compounds of formula XVa andXVb in the presence of in situ generated T1(OTf)3 under acidicconditions according to the procedure of Lee and Hong; TetrahedronLett., (1997), 38, 8959-60.

Alternatively compounds of formula III and XVII are reacted as describedabove for formula V to give an intermediate of formula XVIII. Such anintermediate may give the required oxazole by cyclodehydration with togenerate the oxazoline followed by dehydrogenation using BrCCl₃ in thesame reaction pot. Phillips, A. J.; Uto, Y.; Wipf, P.; Reno, M. J. andWilliams, D. R., Organic Letters, (2000) 2, 1165-8.

Formation of the Bond Between X⁴ and M² or Q and M² Through NucleophilicDisplacement of a Leaving Group:

A compound of formula XX, may be used to displace the leaving group LGin compounds of formula XIX (R⁷ is M¹-(R²)_(n)—P—(R¹)_(m1)). When X⁴ isrepresented by a heteroatom such as N and S, the reaction is carried outin the presence of an appropriate base such as potassium carbonate,cesium carbonate, sodium hydride, triethylamine or the like, which mayfacilitate the reaction by deprotonation of the X⁴ residue and preventthe formation of any excess acid that would be generated by the reactionin the absence of a base. The reaction may be accomplished using anyappropriate solvent such as acetonitrile or DMF, and may be carried outat room temperature or at elevated temperature (35-100° C.) toaccelerate the reaction.

Such conditions may be used with appropriate modifications of employedequipment for parallel synthesis, using standard techniques known to theone skilled in the art.

Similarly these reaction conditions may be carried out for compounds offormula XX when X⁴=bond and ring Q is a fused bicycle containing aheteroatom such as N as defined above. In either the latter or the abovedescribed case with X⁴=N, NaH in DMF is preferred as described inliterature precedences, for example Murdoch, Robert; Tully, W. Roger;Westwood, Robert; J. Heterocycl. Chem.; (1986), 23; 833-841.

For compounds of formula XX containing X⁴=C a stronger base needs to beemployed to achieve deprotonation, such as for example LDA,n-butyllithium or any other alkyl metal base in appropriate aproticsolvents such as THF, hexane or toluene at temperatures generally belowambient temperatures, e.g. at −78° C. or 0° C.

An alternative procedure for the synthesis of above described type ofthiomethyl oxadiazole is to form an acyclic ester IVa and IVb from thecombination of a suitably substituted hydroxyamidine and activated acidcoupling partner also suitably substituted. Displacement of the chlorideusing the thiol nucleophile may occur immediately prior to cyclizationusing one of the methods of oxadiazole formation described above. Thedisplacement can also be carried out on the chloromethyl hydroxyamidineor chloromethyl acid starting materials followed by the two stepesterification and cyclization as above. The conditions described may beused with appropriate modifications of employed equipment for parallelsynthesis using standard techniques known to the one skilled in the art.

Formation of 4-alkyl-triazoles thiols/thiones:

Any suitable acylating agent such as an acid chloride or an activatedacid or the corresponding acid under amide coupling conditions asmentioned above, is reacted with a suitable 4-alkyl-3-thiosemicarbazidein the presence of a base such as pyridine or non-nucleophilic amines toform the acyclic intermediate compound of formula XXV, wherein R⁴ is asdefined above. The same intermediate is also available through reactionof an acyl hydrazide with an alkyl isothiocyanate. Cyclization to give acompound of formula XXVI is easily effected by treatment with anappropriate inorganic base such as hydroxide or bicarbonate at elevatedtemperature in an appropriate solvent such as water, water-dioxane, anaqueous alcohol or mixture thereof.

Such conditions may be used with appropriate modifications of employedequipment when using a solid phase base instead of above-mentioned ones,such as for example P-BEMP for parallel synthesis using standardtechniques known to the one skilled in the art.

The compound of formula XXV reacts through its tautomeric form under theconditions described above with compounds of formula XIX to yield theS-alkylation compounds of the formula Ia.

The triazole thiones XXIX and XXXI alkylated on the other nitrogen atomsof the ring (1 and 2) are available through similar procedures. The2-alkyl triazole thione XXVIII may be obtained by treatment of an aroylisothiocyanate with an alkyl hydrazine in toluene at elevatedtemperatures, e.g. 85° C., followed by heating with aqueous bicarbonate.The same product may also be obtained through treatment of the analogous2-alkyl-3-thiosemicarbazide with an activated acid in the presence of asuitable base such as pyridine or triethylamine followed by alkalinering closure in a manner similar to the alkaline ring closure yieldingproduct XXVI above.

The 1-alkyl triazole thiones XXXI may be prepared by the reaction of asuitable N-alkyl-N-acylhydrazide with potassium thiocyanate in thepresence of an acid such as HCl or other compatible strong acid via the1-acyl-1-alkyl-3-thoisemicarbazide intermediate which undergoes alkalinering closure in a manner the alkaline ring closure yielding compounds offormula XXVI above.

Formation of Compounds of Formula XXXIII

A compound of formula XXXIII may be prepared by alkylation of cyclicthioureas of formula XXXIIa, wherein n is defined as 0, 1 or 2,resulting in compound of formula XXXIIb, e.g.2-methylthio-1,4,5,6-tetrahydropyrimidine in case of n=1. The alkylationwith for example methyliodide as alkylating agent can be done in severalsolvents (DMF, acetone, CH₂Cl₂ etc.) at room temperature or elevatedtemperatures and will give the product as its hydroiodide salt as hasbeen previously described by Kennedy, Kevin J.; Simandan, Tiberiu L.;Dix, Thomas A.; Synth. Commun.; (1998); 24; 741-746. Cyclic thioureasare readily available either through synthesis as known by the oneskilled in the art, or commercial sources. Compounds of formula XXXIIcresult from the hydrazinolysis of the corresponding compounds of typeXXXIIb. The hydrazinolysis is preferably done in refluxing EtOH withhydrazine hydrate as described previously by Krezel, Izabella;Pharmazie; (1994); 94, 27-31. Finally, fused triazoles of formula XXXIIImay be formed through the thermal acylation and condensation reactionbetween compounds of formula XXI wherein LG is a leaving group as forexample a halide, and compounds of formula XXXIIc. Such reactions may beconducted in pyridine or in EtOH or toluene in the presence of base.Normal heating or microwave irradiation may be used. Similarly, XXXIIImay be prepared in the presence of a base, such as sodium methoxide in asuitable solvent such as methanol or ethanol at elevated temperatureswhere XXI may also be an ester or carboxylic acid.

Acyclic thioureas of formula XXXIId, wherein R⁸ is defined as in thescheme and R³ and R⁴ are as defined in Formula I, may also be employedusing a similar method to obtain compounds of formula XXXIIIa, whereinthe introduction of the hydrazine portion may be carried out usingeither hydrazine followed by acylation, or by using a preformed acylhydrazine.

Formation of Compounds of Formula XXXV

Compounds of formula XXXIVb may be prepared by using similar methods asabove, e.g. by activation of XXXIVa to give the corresponding imidoylchloride by using oxalyl chloride or pentachlorophosphine in theoptional presence of a base such as triethylamine. The intermediate maybe used in-situ or may be isolated prior to trapping by a compound offormula XXIII as has been used above. The subsequent product may becyclized under acidic or basic conditions in a suitable solvent such asDMF to give compounds of formula XXXV. XXXV may be an intermediate usedin the formation of compounds of Formula I, or may be the finalbioactive compound of Formula I.

A compound of formula XXXV, wherein R⁸ is selected independently from agroup as depicted above may also be prepared through reaction ofcompounds of formula XXXVIa (ethyl imidoate is depicted as example) andXXXVIb followed by cyclization at elevated temperatures (40-80° C.) inthe presence of an amine, whereas the amine preferably should have, butis not limited to, a low boiling point such as that it can be used inexcess and simplify the work-up procedure. Examples for such amines maybe, but are not limited to methylamine or ethylamine which may be usedas solutions in for example methanol, THF or dichloromethane.

Formation of Compounds of Formula XXXVIa and XXXVIb

A compound of formula XXXVIa, wherein R⁸ is selected independently froma group as depicted above may be prepared through reaction of a nitrileof formula XXXVIe in an alcohol such as ethanol in the presence of aprotic acid, for example hydrochloric acid. The nitrile may be obtainedfrom an acid XXXVId as described above. Compounds of formula XXXVId mayalso be used to prepare acyl hydrazides of formula XXXVIb, wherein R⁸ isselected independently from a group as depicted above. This type ofsubstance XXXVIb may also be formed directly from an acid. There may beadvantages to react an intermediate ester of type XXXVIf with eitherneat hydrazine, hydrazine salt in the presence of a base or hydrazinehydrate in facilitating a simpler workup. However, the direct route viathe acid using in situ activation may be advantageous in substratessensitive to nucleophilic attack and also give the product in a shortersequence of steps.

Formation of Compounds of Formula XXXVId and XXXVIf

Compound of formula XXXVId & XXXVIf, wherein R⁷ is a group consisting ofM¹-(R²)_(n)—P—(R¹)_(m), may be prepared by either of the non-limitingmethods: a) reaction of acyl hydrazide compounds of formula XII with acyclic anhydride or monoesterified diacid followed by the cyclization ofthe formed intermediate would lead to 1,3,4-oxadiazoles of type XXXVIdand XXXVIf respectively (X¹=O, X² and X³=N); b) reaction and cyclizationof an hydroxyamidine of Formula II with a cyclic anhydride or with themonoesterified diacid may be used to provide the 1,2,4-oxaziazoleanalogs XXXVId and XXXVIf wherein X¹ and X²=N, X³=O; c) reaction of acompound of type III with an hydroxamidine type compound, with theexception of the succinyl derivative, may be used to provide the1,2,4-oxaziazole analogs XXXVIf wherein X¹ and X³=N, X²=O. CompoundsXXXVId and XXXVIf may be interconverted independent of the nature of X¹,X² or X³ as described above.

Formation of Compounds of Formula Ib

A compound of formula Ib, wherein R⁷ is selected from a groupM¹-(R²)_(n)—P—(R¹)_(m1) may be prepared from compounds of formulaXXXVII, generated from XIV as described below, through selective Oalkylation using Me₃OBF₄ or dimethyl sulfate (as described in literatureprecedences, for example: a) Sheu, Jennline; Smith, Michael B.;Oeschger, Thomas R.; Satchell, Jacqueline; Org. Prep. Proced. Int.;(1992); 24, 147-158; or b) Hutchinson, Ian S.; Matlin, Stephen A.; Mete,Antonio, Tetrahedron Lett.; (2001); 42; 1773-1776). The methoxy groupmay then be displaced by an acyl hydrazide of type XXIII, followed by aring closing condensation to form the triazole heterocycle. This may bedone in ethanol, toluene, DMF or pyridine under thermal conditions withregular heating or microwave irradiation, as has been previouslydescribed by for example Lawson, Edward C.; Hoekstra, William J.; Addo,Michael F.; Andrade-Gordon, Patricia; Damiano, Bruce P.; Kauffman, JackA.; Mitchell, John A.; Maryanoff, Bruce E.; Bioorg. Med. Chem. Lett.;(2001); 11; 2619-2622.

One preferred subset of compounds of formula Ib are those of formula gand can be made according to the following scheme:

Compounds of formula b may be generated through selective O alkylationof a cyclic lactam a using Me₃OBF₄ or dimethyl sulfate (as described inliterature precedences, for example: a) Sheu, Jennline; Smith, MichaelB.; Oeschger, Thomas R.; Satchell, Jacqueline; Org. Prep. Proced. Int.;(1992); 24, 147-158; or b) Hutchinson, Ian S.; Matlin, Stephen A.; Mete,Antonio, Tetrahedron Lett.; (2001); 42; 1773-1776). The methoxy groupmay then be displaced by or hydrazine to form intermediate c which canbe acylated to provide intermediate d. Alternatively the methoxy groupmay be displaced using an acyl hydrazide to yield d directly. Ringclosing condensation to form the triazole heterocycle e may be done inethanol, toluene, DMF or pyridine under thermal conditions with regularheating or microwave irradiation, as has been previously described byfor example Lawson, Edward C.; Hoekstra, William J.; Addo, Michael F.;Andrade-Gordon, Patricia; Damiano, Bruce P.; Kauffman, Jack A.;Mitchell, John A.; Maryanoff, Bruce E.; Bioorg. Med. Chem. Lett.;(2001); 11; 2619-2622.

A compound of formula g, wherein R⁷ is selected from a groupM¹-(R²)_(n)—P—(R¹)m₁ may be prepared from compounds of formula e, bydeprotonation and reaction with compounds of formula f. Although thiscan be accomplished using a strong base due to the stabilization of thearomatic triazole ring, the reaction is facilitated when R is a groupwhich provides additional stabilization of the resulting carbanions,such as an ester, nitrile or sulfone.

Compounds of type XXXVII may be prepared by the reaction of cyclicamides, lactams, which are readily alkylated in the α-position to thecarbonyl by successive treatment with 2 equivalents of a strong basee.g. n-Buli to generate the dianion followed by addition of 1 equivalentof compounds of formula XIX, in an aprotic solvent such as THF, as hasbeen previously described by for example Grieco, Paul A.; Kaufman,Michael D.; J. Org. Chem.; (1999); 64; 6041-6048). Alternatively, aN-protected lactam may be used in which only 1 equivalent base e.g. LDAis needed to generate the anion for the alkylation as has beenpreviously described by for example Padwa, Albert; Beall, L. Scott;Heidelbaugh, Todd M.; Liu, Bing; Sheehan, Scott M.; J. Org. Chem.;(2000); 65; 2684-2695.

General Synthesis of Compounds of Formula Ic

A compound of formula Ic, wherein R⁷ is consisting ofM¹-(R²)_(n)—P—(R¹)_(m1), may be prepared through reaction withsubsequent cyclization of compounds of formula XXXVIII, with a compoundof formula XXXIX. The compound of formula XXXIX may be prepared from asuitable secondary amide using oxalyl chloride or pentachlorophosphinein the optional presence of a base such as triethylamine and used eitherin-situ or as isolated material as described above from XXXIVa.

Compounds of formula XXXVIII, may be prepared from the correspondingalcohol by reacting it with phosgene or preferably a phosgene analogsuch as carbonyldiimidazole followed by coupling to hydrazine.

Other means of synthesizing a compound of formula Ic or Id, wherein X⁴=Oand wherein R⁷ is M¹-(R²)_(n)—P—(R¹)_(m1), may be by the O-alkylation ofcompounds of type XL with compounds of type XLI wherein the leavinggroup may consist of a tosyl-, mesyl-, halo- or any other appropriategroup, in the a suitable base such as cesium or potassium carbonate,sodium hydride in solvents such as for example DMF or DMSO.

Compounds of type XLI may be synthesized as exemplified with triazoleXXVI by alkylation or arylation of the sulfur group using an appropriatealkylating or arylating reagent followed by double oxidation of thethiogroup to the corresponding sulfone using oxidants such as MCPBA,hydrogen peroxide in acetic acid or potassium permanganate. Such asequence has previously been described for example by Åkerblom et al. J.Med. Chem. 16, 312 (1973). Alternatively, triazole halides may besynthesized as previously described in the literature by for exampleAshton, W. T. et al. J. Med. Chem. 36, 591 (1993).

The alcohols may be prepared either directly upon synthesis of theoxadiazole or isoxazole part as described above under general synthesisof compounds of formula V. Alternatively they may be prepared from anoxadiazole or isoxazole unit with an appropriate leaving group such as ahalide, e.g. chloride, using a three step sequence as described byPalazzo et al. J. Heterocycl. Chem. (1979) 16:1469, followed by astandard reduction protocol of the resulting aldehyde (or hydratethereof) using for example sodium borohydride in methanol.

Yet another method may involve the reaction of a compound of structureXIV unit containing an appropriate leaving group such as a halide, e.g.chloride with hydroxybenzotriazole in the presence of a suitable basesuch as potassium carbonate or triethylamine in a suitable solvent suchas DMSO, acetonitrile, acetone, DMF to give compounds of type XLa.Alternatively XLa may be obtained if hydroxybenzotriazole is presentduring cyclization to the oxadiazole, either as a co-activator with EDCIor as a result of a byproduct from a coupling reagent such as HBTU asdescribed above under the reaction of compounds of formula II-V. XLa maybe converted to the alcohol by the addition of samarium diiode,preferably over an elongated period of time (5-360 minutes) in asuitable solvent such as tetrahydrofuran, methanol, water or mixturesthereof, with THF being a preferred solvent, at an appropriatetemperature (−75° C.-+75° C.).

The cleavage of the N—O bond can alternatively be done using commonlyused hydrogenation methods in the presence of a suitable catalyst suchas raney-nickel as known by the one skilled in the art. In compounds offormula XLa the oxobenzotriazole functionality may also serve as aleaving group. Thus compounds XLa may react with compounds XX asdescribed above.

Formation of Compounds of Type Ie

A compound of formula Ie, wherein R⁷ is M¹-(R²)_(n)—P—(R¹)_(m1), may beprepared through nucleophilic substitution of compounds of type XLIIIbwith compounds of type XIX as described above. Compounds of type XLIIIbmay be prepared by reaction of their oxo-analogues XLIIIa using P₂S₁₀ orLawesson's reagent under thermal conditions. Synthesis of compounds oftype XLIIIa has been described by Takeuchi, H., Hagiwara, S., Eguchi,S., Tetrahedron (1989); 45; 6375-6386.

Introduction of Substitution in the Q Ring:

If substitution on the Q ring is desired, one may choose anappropriately substituted aryl or heteroaryl thiol to use for thedisplacement reaction. The same is valid for other nucleophilic reagentsother than substituted or non-substituted aryl or heteroaryl thiolsserving to substitute the same in the final compounds. If the aryl orheteroaryl residue has an amenable reactive moiety, either directlyintroduced or as a result of a deprotection reaction, including but notlimited to a free NH site as in aniline, imidazole, benzimidazole,indole and the like, a compound of formula If (R⁷ isM¹-(R²)_(n)—P—(R¹)_(m1)) may be substituted with R⁴ using a suitablebase such as an alkyllithium or alkali-metal hydride or hydroxide todeprotonate the NH residue, followed by the addition of a suitableelectrophilic reagent such as an alkyl halides, acid chlorides oranhydrides, chloroformates, carbamoyl chlorides, sulfonyl chlorides,isocyanates, isothiocyanates and the like to provide the substitutedproduct of Formula Ia.

Introduction of the M² Substituent(s) and of the X Substituent(s):

When the most acidic protons are positioned on the atom adjacent to X⁴,or on X⁴ itself, substitution may be achieved by deprotonation ofcompound of Formula Ia with a strong base such as an alkyllithium or analkali-metal hydride in a suitable aprotic non-acidic solvent like THFor diethylether followed by trapping of the resulting anion with asuitable electrophile such as alkyl halides, acid chlorides oranhydrides, chloroformates, carbamoyl chlorides, sulfonyl chlorides,isocyanates, isothiocyanates and the like. When an excess of base andelectrophile are employed and the reaction is left for sufficient time,two hydrogens may be replaced by the electrophile as illustrated belowfor the introduction of two R³-substituents (M² exemplified as carbon).Two or more, different or same substituents, might also be introducedaccordingly by subsequent deprotonations and reactions with appropriateelectrophiles to yield compounds of Formula Ig.

Oxidation of S Atom of Chain (when X is S) or N Atoms on Substituents:

Oxidation of the sulfur atom to give sulfones (Y=O) and sulfoxides(Y=“:”, i.e. a lone pair) may be achieved by direct oxidation using anysuitable oxidizing agent including peroxyacids such as MCPBA. In thecase of MCPBA oxidation, it is possible to obtain a mixture of productsfrom a single reaction and separate them by standard columnchromatography or to obtain selectively the sulfoxide or sulfone bycontrolling the stoichiometry and temperature of the reaction.

If one of the substitutents, e.g. R⁴ contains one or more nitrogen atomsas for example a pyridine moiety or any other substituent as definedabove, then oxidation of this nitrogen may occur in the above reactionof Ia with an oxidant such as MCPBA to give the corresponding N-oxide.It is understood to the one skilled in the art that such products may beobtained by separation via standard column chromatography or any otherstandard purification protocol even in the case of mixtures containingfor example Ih and N-oxide. It is also understood to the skilled in theart that the formation of N-oxides may be reduced by choice of suitablereaction conditions such as using acidic media to protect the nasicamine.

Other Miscellaneous Reactions:

When the intermediate compounds contain a suitable reactivefunctionality such as an aryl halide or triflate, the functionality maybe employed to further elaborate the product. For example, when3-halo-phenyl is present in P—(R¹)_(m1), it is possible to use standardSuzuki conditions to couple an aryl boronic acid to yield a diarylcoupling product. Miyaura, N., Yanagi, T., Suzuki, A., Synth. Commun.,(1981), 11; 7, 513-520.

Other functionalities such as an aliphatic alcohol may for example beconverted to a fluoro group by the use of a fluorinating agent such asDAST, or other halide groups by the use of for exampletriphenylphosphine and either iodine, N-bromosuccinimide orN-chlorosuccinimide These halides may serve as leaving groups forfurther elaboration or may remain as substituent in active compounds offormula Ia.

In a similar fashion alcohols may be transformed to leaving grous suchas the non-limiting examples mesyl or tosyl by employing the appropriatesulfonyl halide or sulfonyl anhydride in the presence of anon-nucleophilic base together with the alcohol to obtain the sulfonicester derivative.

Other functionalities which may be further elaborated are depicted inthe following, non-limiting example (R⁷ is M¹-(R²)_(n)—P—(R¹)_(m1)),where halogenation may be undergone on a carbon-atom of an oxazole unitemploying a chlorinating agent such as sulfuryl chloride.

Additional Reactions for the Preparation of Intermediate and FinalCompounds

More specific reaction types useful for the preparation of compounds offormula I and their intermediates, where applicable, are given below inthe synthetic schemes and their corresponding descriptions. Thedefinitions in the following formula are as defined in formula unlessotherwise specified. Other starting materials are either commerciallyavailable or can be prepared via methods described in the literature.

Intermediate Compounds

Alkylsulphonyl[1,2,4]triazoles

With reference to scheme 1, alkylsulphonyl[1,2,4]triazoles can beprepared from the corresponding [1,2,4]triazolethiones by initialalkylation of the sulphur atom with primary alkyl halides such as MeIand EtI (alkyl is Me and Et respectively) in MeOH, EtOH, THF, acetone orthe like at −30 to 100° C., followed by oxidation of the sulphur atomusing for example KMnO₄ in mixtures of water and acetic acid, or mCPBAin DCM, at −20 to 120° C., or by using any other suitable oxidant.[1,2,4]triazolethiones are for example prepared by N-acylation of athiosemicarbazide, using any suitable acylating agent such as acidchlorides (LG is Cl) in for example pyridine, or acids (LG is OH), thatare activated by the treatment with standard activating reagents asdescribed herein below, in DMF, THF, DCM or the like at −20 to 120° C.,followed by ring closure of the initially formed acyclic intermediateeither spontaneously under the conditions of the acylation, or byheating at 50 to 150° C. in pyridine or in aqueous solvents in thepresence of a base, such as NaHCO₃ or Na₂CO₃, with or withoutco-solvents such as dioxane, THF, MeOH, EtOH or DMF. This acyclicintermediate can also be formed by treatment of the proper acylhydrazide with a suitable isothiocyanate in for example 2-propanol, DCM,THF or the like at −20 to 120° C.

Amino[1, 2, 4]triazoles

With reference to scheme 2, amino[1,2,4]triazoles are obtained bytreating carbonohydrazonic diamides with a proper acylating agentcarrying a leaving group LG in suitable solvent such as THF, pyridine orDMF at −20 to 100° C. The reaction initially leads to an openintermediate that either forms a triazole ring spontaneously, or can bemade to do so by heating at 50 to 200° C. in for example pyridine orDMF. The leaving group LG may be chloro or any other suitable leavinggroup as for example generated by in situ treatment of the correspondingacid (LG is OH) with standard activating reagents as described hereinbelow. Carbonohydrazonic diamides may be generated from isothioureas, inwhich the S-alkyl (for example S-Me or S-Et) moiety acts as a leavinggroup upon treatment with hydrazine in solvents such as pyridine,methanol, ethanol, 2-propanol, THF or the like at −20 to 180° C. Theopen intermediate can also be directly generated by treatment ofisothioureas with acylhydrazines under the same conditions as describedfor the reaction with hydrazine. Isothioureas are obtained byS-alkylation of the corresponding thioureas with for example MeI or EtIin acetone, EtOH, THF, DCM or the like at −100 to 100° C.

Carbon Substituted [1,2,4]triazoles

With reference to scheme 3, imidoyl chlorides react with acyl hydrazidesin suitable solvents, such as THF, pyridine or DMF at −20 to 100° C. toinitially form an open intermediate that either forms a triazole ringspontaneously, or can be made to do so by heating at 50 to 200° C. infor example pyridine, DMF or water, with or without the presence of abase such as NaHCO₃ or Na₂CO₃. Imidoylchlorides may in turn be obtainedfrom the corresponding amides by standard methods such as by treatmentwith oxalyl chloride or thionyl chloride.

Imidazole-4-carbaldehydes and [1,2,4]triazolecarbaldehydes

With reference to scheme 4, Imidazole-4-carbaldehydes (X⁵ is C) are forexample prepared by reacting suitably substituted amidines with2-bromo-3-isopropoxyacrylaldehyde in for example well-stirred mixturesof an organic solvent, such as chloroform, DCM, or toluene and water inthe presence of a base such as a carbonate at 10 to 100° C. The amidinestarting material might be prepared using standard methods from thecorresponding nitrile via the imidate ester (alkyl is for example Me orEt), by treatment with for example a hydrochloric acid solution in thecorresponding alcohol solvent followed by treatment with an aminesubstituted with the group R⁵, or directly from the correspondingnitrile by reacting with the same amine together with trimethylaluminum.[1,2,4]triazolecarbaldehydes (X⁵ is N) can be prepared by oxidizing thecorresponding primary alcohols, using for example MnO₂ or any otherstandard oxidant for this type of transformation. These alcohols, inturn, may be prepared by hydroxymethylation of the corresponding Cunsubstituted triazoles using for example formaline at elevatedtemperature. C unsubstituted triazoles are for example prepared throughstandard desulphurization of [1,2,4]triazolethiones with Raney-Ni.

Isoxazole-5-carboxylic Acid Esters

In reference to scheme 5, isoxazoles are formed by reaction and in-situcyclization of dioxo butyric ester derivatives with hydroxylaminehydrochloride in solvents such as ethanol, 2-propanol or DMF attemperatures from 40 to 140° C. Dioxo butyric esters are formed throughthe reaction of acetophenones with dialkyl oxolates (alkyl is forexample Me or Et) in the presence of a strong base such as sodiumhydride in solvents such as DMF or toluene at temperatures from −20 to120° C.

Carbon Substituted [1,2,4]oxadiazoles

With reference to scheme 6, [1,2,4]oxadiazoles with a carbon alpha tothe heterocycle, wherein G¹, G² and G³ are defined as described inscheme 6, are formed by cyclization of G¹- andG²-substituted-acyloxyimidamides in solvents such as pyridine, DMF, orwater containing mixtures thereof, at 40 to 140° C., alternatively inaqueous alcoholic solvents in the presence of sodium acetate attemperatures from 40 to 140° C., with the later method being preferredif one of the groups G¹ or G² contains a chiral stereocenter.Acyloxyimidamides are formed by coupling with a proper acylating agentcarrying a leaving group LG with a G¹-substituted hydroxamidine. Theleaving group LG may be chloro or any other suitable leaving group asfor example generated by in situ treatment of the corresponding acid (LGis OH) with standard activating reagents as described herein below.G¹-substituted hydroxamidines are formed by reaction of thecorresponding nitrile with the free base of hydroxylamine, orhydroxylamine hydrochloride in the presence of a base such astriethylamine, pyridine or sodium carbonate, in solvents such asethanol, water or pyridine at temperatures from −20 to 120° C.

Amino[1, 2, 4]oxadiazoles

With reference to scheme 7, amino[1,2,4]oxadiazoles are obtained fromthe corresponding bromo[1,2,4]oxadiazoles by reaction with an excessalkylamine in solvents such as methanol or ethanol at elevatedtemperatures. Intermediate bromo[1,2,4]oxadiazoles are obtained byreaction of benzonitrile derivatives with hydroxycarbonimidic dibromidein the presence of a base such as NaHCO₃ in solvents such as toluene orDMF at elevated temperatures.

Carbon substituted [1,3,4]oxadiazoles

With reference to scheme 8, starting from acid hydrazides, coupling withan aliphatic acid chloride derivative in THF, DMF, toluene or the like,optionally in the presence of a base such as triethylamine or acarbonate, leads to the formation of an acyl benzohydrazide derivative,which is cyclized at elevated temperatures in the presence of adehydrating agent such as phosphorous pentoxide in solvents such astoluene or DMF or mixtures thereof to yield the [1,3,4]oxadiazoleproduct. Alternatively, [1,3,4]oxadiazoles may be made directly from theacid hydrazide using trialkyl ortho esters either neat or in solventssuch as toluene or xylenes at elevated temperatures.

Functional Group Transformations

With reference to scheme 9, aliphatic alcohols may for example beconverted by standard methods to the corresponding halides by the use offor example triphenylphosphine in combination with either iodine,N-bromosuccinimide or N-chlorosuccinimide, or alternatively by treatmentwith tribromo phosphine or thionylchloride. In a similar fashionalcohols may be transformed to other leaving groups such as mesylates ortosylates by employing the appropriate sulfonyl halide or sulfonylanhydride in the presence of a non-nucleophilic base together with thealcohol to obtain the corresponding sulfonates. Clorides or sulphonatescan be converted to the corresponding bromides or iodides by treatmentwith bromide salts, for example LiBr, or iodide salts. Further standardmethods to obtain alcohols include the reduction of the correspondingcarbonyl containing groups such as methyl or ethyl esters, aldehydes (R³is H) or ketones (R³ is not H), by employing common reducing agents suchas boranes, lithium borohydride, lithium aluminumhydride, or hydrogen inthe presence of a transition metal catalyst such as complexes of forexample ruthenium or iridium, or alternatively palladium on charcoal.

Stereoselective Preparation of Chiral Secondary Alcohols

Enantiomerically pure or enriched products as depicted in scheme 10 (R³is Me or Et) are obtained by kinetic resolution of racemic or scalemicsecondary alcohols using enzyme-catalyzed acetylation with for examplepolymer bound Candida Antarctica Lipase (Novozyme 435®), or otheresterases, for example Candida rugosa or Pseudomonas fluorescens, inorganic solvents such as toluene, tert-butyl methyl ether, tert-butanolor DCM at temperatures from 0 to 90° C., using acetylating reagents suchas vinyl acetate, other substituted alkyl acetates, pentafluorophenylacetate or nitro- or halophenyl acetates, which yields the enriched(R)-acetate and the enriched (S)-alcohol. The (R)-acetate may behydrolyzed to the corresponding alcohol by e.g. lithium hydroxide inmixtures of THF and water or by any other methods as described hereinbelow, to yield the opposite enantiomerically enriched or pure alcohol.

Isothioureas

Isothioureas, as depicted in scheme 11, may be obtained by substitutionof a leaving group LG (LG is for example Cl, Br or OMs) by aR⁴-substituted amine in solvents such as MeOH or EtOH at temperaturesfrom 0 to 150° C. The product is added to an isocyanate substituted withR⁵ in solvents such as chloroform, ethanol, methanol or DMF attemperatures from −20 to 100° C., yielding a thiourea intermediate,which may be alkylated by an alkylating agent such as methyl- orethyliodide or any other suitable primary alkyl halide or sulphonate, insolvents such as methanol, ethanol, acetonitrile or acetone, in thepresence or absence of a base such as triethylamine or potassiumcarbonate.

Propionic Acid Derivatives

Propionic acid derivatives such as saturated alkyl esters, saturatedfree carboxylic acids or saturated acyl hydrazides may be prepared asdepicted in scheme 12. Carboxylic acids are obtained upon hydrolysis ofthe corresponding esters for example under basic conditions such assodium hydroxide in methanol or any other method known to the oneskilled in the art. The corresponding saturated alkyl esters in turn maybe obtained from the unsaturated ester by reduction of the carbon-carbondouble bond using hydrogen at atmospheric pressure or elevated pressuresup to 100 bars in the presence of a metal catalyst such as palladium oncharcoal or any other selective reducing agent suitable for this type ofcompounds as known to the one skilled in the art. During aforementionedhydrogenation, any halide substituents attached to aromatic groups R⁶will be removed by hydro-dehalogenation. Unsaturated esters in turn maybe obtained by an olefination reaction such as the Wittig orHorner-Wadsworth-Emmons type by reacting an aldehyde or ketone in thepresence of a suitable base such as n-BuLi or DBU with appropriatelysubstituted phosphor ylides or phosphonates such astriethyl-2-phosphonopropionate, or 2-(diethoxy-phosphoryl)-propionicacid ethyl ester in suitable solvents such as acetonititrile or THF attemperatures from −90 to 100° C. Acyl hydrazides may be obtained fromthe corresponding esters by reaction with hydrazine, or from the freecarboxylic acids by activation as described herein below and couplingwith hydrazine.

Preparation of Final Compounds

Several non-limiting methods for preparing the final compounds areillustrated and exemplified by drawings in which the generic groups, orother structural elements of the intermediates correspond to those offormula I. It is to be understood that an intermediate containing anyother generic group or structural element than those of formula I can beused in the exemplified reactions, provided that this group or elementdoes not hinder the reaction and that it can be chemically converted tothe corresponding group or element of formula I at a later stage whichis known to the one skilled in the art.

By Connection to Nucleophilic X⁴

With reference to scheme 13, compounds of formula I can be prepared bybond formation through nucleophilic replacement of a leaving group (LG)in which X⁴ is acting as nucleophile. X⁴ can be a carbon or nitrogenatom in it's anionic form, generated by treatment of the correspondingprotonated neutral atom with bases in suitable solvents such as LDA ornBuLi in THF, diethylether or toluene, or NaH in for example DMF, orK₂CO₃ in acetonitile or ketones such as 2-butanone at a temperature from−100 to 150° C. When X⁴ is carbon, LG is preferable bromo, and when X⁴is nitrogen examples of suitable leaving groups LG are chloro, bromo,OMs and OTs. When X⁴ is N, the reaction may also be undertaken in astereoselective manner by employing enantiomerically pure or enrichedstarting materials in which the leaving group LG is attached to thestereocenter. Optionally, catalytic or stoichiometric amounts of analkali metal iodide, such as LiI, can be present in the reaction tofacilitate the same through in situ displacement of the leaving group toiodo.

By Connection to Nucleophilic Oxygen

With reference to scheme 14, compounds of formula I can be prepared bybond formation through nucleophilic replacement of a leaving group (LG)in which an alcohol is acting as O-nucleophile under basic conditions tofacilitate the reaction. As base, for example NaH or Cs₂CO₃ is used, thelatter being preferred for obtaining enantiomerically pure products, attemperatures from 0 to 100° C. in polar aprotic solvents such as DMF oracetonitrile. Examples of suitable leaving groups are sulphonates suchas OMs and halogens such as chloro.

By Alpha-Alkylation Relative to Ring Q

With reference to scheme 15, compounds of formula I substituted with nogroup R³ can be either mono- or dialkylated at the position alpha toring Q. Dialkylation can be performed sequentially for the introductionof two different or same groups R³. Preferably, primary alkyl halides,mesylates, or tosylates are used as alkylating reagents (R³-LG) in thereaction with an intermediate carbanionic nucleophile generated upontreatment of compounds of formula I, substituted with no or one groupR³, with strong bases such as NaH, LDA or HMDS alkali metal salts insolvents such as for example THF, diethylether, hexanes or toluene at atemperature of −100 to 50° C.

By Formation of a Triazole Ring

With reference to scheme 16, intermediates carrying a leaving group LG¹,such as SMe or SEt, can undergo reaction with hydrazine in solvents suchas pyridine, methanol, ethanol, 2-propanol, THF or the like at −20 to180° C. Subsequent acylation with an acylating agent carrying a leavinggroup LG² in suitable solvent such as THF, pyridine or DMF at 0 to 100°C. leads to an open intermediate that either forms a triazole ringspontaneously, or can be whipped to do so by heating at 50 to 200° C.,resulting in the formation of a compound of formula I. LG² may be chloroor any other suitable leaving group as for example generated by in situtreatment of the corresponding acid (LG²=OH) with standard activatingreagents such as DCC, DIC, EDCI or HBTU, with or without the presence ofco-reagents such as HOBt or DMAP in suitable solvents such as DMF, DCM,THF, or acetonitrile at a temperature from −20 to 100° C. Alternatively,acylhydrazines can be directly reacted with intermediates carrying aleaving group LG¹ under the conditions described above to yieldcompounds of formula I.

By Formation of the Ring Q

With reference to scheme 17, the ring Q of compounds of formula I may beformed by reaction of esters (G is for example OMe or OEt) or activatedacid derivatives, such as acid chlorides (G is Cl) or else as generatedupon treatment of the corresponding acids (G is OH) with standardactivating reagents as described herein above, with N-hydroxyamidines.When employing esters, suitable conditions include the use of thesolvents 1-propanol, 2-propanol, EtOH or toluene, together with astoichiometric amount of a base such as potassium tert-butoxide at 0 to180° C. When employing activated acid derivatives the reaction can forexample be run in DMF, DCM, THF, pyridine or the like at −20 to 120° C.The initially formed acyclic intermediate may ringclose spontaneously toform an [1,2,4]oxadiazole, or may be heated in pyridine, DMF, EtOH, MeOHor aqueous mixtures thereof, with or without additives such as sodiumacetate, at 50 to 200° C. Upon reaction of acyl hydrazides (G is NHNH₂)with imidate esters (alkyl is for example Me or Et), or thecorresponding salts, in MeOH, EtOH, THF, DMF or the like at 0 to 150°C., compounds of formula I in which the ring Q is [1,3,4]oxadiazole aregenerated.

By N-alkylation of Heterocyclic Amines

With reference to scheme 18, compounds of formula I are prepared by bondformation through nucleophilic replacement of a leaving group (LG) inwhich the nitrogen atom, to which the group R³ is attached, is acting asnucleophile. The reaction is facilitated by deprotonation of thisnitrogen atom to generate a stronger nucleophile by treatment with basesin suitable solvents such as LDA, alkali metal salts of HMDS or nBuLi inTHF, diethylether or toluene, or NaH in for example DMF at a temperaturefrom −100 to 150° C. Suitable leaving groups include for example chloro,bromo, iodo, OMs or OTs. Useful intermediates carrying such a leavinggroup can for example be prepared by halogenation of the correspondingcompound in which LG is hydrogen. For example, alpha-chloro triazoles(LG is Cl and X⁵ is N) can be prepared by treatment with SO₂Cl₂ insolvents such as DCM and DMF.

By Cytochrome P450 Mediated Dealkylation

Compounds of formula I in which X⁴ is nitrogen and R⁴ is alkyl,preferably methyl, can be converted to the corresponding compounds inwhich R⁴ is hydrogen by incubation with human liver microsome protein,or other sources of cytochrome P450 isoenzymes including preferably the3A4 isoenzyme, at 35-40° C. in for example aqueous phosphate buffer inthe presence of NADPH.

By Chromatographic Separation of Enantiomers

Practically pure (>95%) enantiomers of compounds of formula I can beobtained by chromatographic separation of the corresponding racemic orscalemic mixtures by using for example Chiralpak AD® or Chiracel OJ® asstationary phase and for example 2-propanol or ethanol, and mixtures ofhexanes and ethanol respectively, as eluants.

EXAMPLES

Suitable embodiments of the invention will now be illustrated by thefollowing non-limiting examples.

NMR measurements were made on the delta scale (δ).

The compounds prepared according to Examples 1 to 39 and 100 to 328 areintermediates.

The compounds prepared according to Examples 40 to 99 and 329 to 794 areend products.

Intermediates

Example 1 6-Methylpyridine-4-carboxylic acid

A hydrogen filled balloon was attached to a flask containing2-chloro-6-methylpyridine-4-carboxylic acid (2 g, 12.0 mmol), palladium10 wt. % on activated carbon (0.5 g), triethyl amine (4.8 ml) andethanol (24 ml) and then stirred overnight at room temperature. Thereaction mixture was filtered through celite, washed with methanol andconcentrated. The residue was titurated with dichloromethane and thenfiltered to afford 6-methylpyridine-4-carboxylic acid as a white solid;1.05 g (66%). ¹H NMR (MeOD) δ (ppm): 8.62 (d, 1H), 7.68 (s, 1H), 7.60(d, 1H), 2.55 (s, 3H).

Example 2 1-Cyano-3-ethylbenzene

Argon was bubbled into a solution of 1-bromo-3-ethylbenzene (2.5 g, 13.5mmol) in DMF (37 ml) for 10 min. and then zinc cyanide (1.75 g, 14.9mmol) and tetrakis(triphenylphosphine)palladium(0) (1.56 g, 1.35 mmol)were added. After stirring at 80° C. overnight the reaction mixture wasdiluted with ethyl acetate (35 ml) then filtered through celite toremove the precipitate. The filtrate was washed with water (3×),saturated brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The product was purified by flash column chromatographyusing 2% ethyl acetate in hexane affording a colorless liquid (1.42 g).GC-MS (M+): 131.18.

Example 3 3-Ethylbenzoic acid

6 M Sodium hydroxide (25 ml) was added to 1-cyano-3-ethylbenzene (1 g,7.62 mmol) in methanol (25 ml) and then heated at 100° C. overnight.After concentrating the reaction mixture, the aqueous layer was washedwith dichloromethane (2×), then acidified pH about 3 with 12 M HCl. Theprecipitate was extracted with ethyl acetate then washed with water andsaturated brine, dried over anhydrous sodium sulfate, filtered andconcentrated to afford 3-ethylbenzoic acid as a colorless oil; 0.770 g(28% yield over 2 steps). ¹H NMR (CDCl₃), δ (ppm): 7.76 (d, 2H), 7.43(m, 2H), 2.67 (m, 2H), 1.19 (t, 3H).

Example 4 3-Fluoro-5-methyl-benzoic acid

Concentrated HCl (30 ml) was added to a cooled (−5° C.) suspension ofdimethyl 5-amino isophthalate (20 g, 95.6 mmol) in water (75 ml),followed by portionwise addition of NaNO₂ (7.5 g, 109 mmol). Thereaction mixture was then stirred for 15 min., after which HBF₄ (18 ml,100 mmol, 48% aqueous solution) was added. The resulting mixture wasstirred at 0° C. for 30 min. and the precipitate formed was collected byfiltration and washed with cold methanol (60 ml) and ether (60 ml). Theresidue was then decomposed by heating in an oil bath (˜110° C.). Thecooled mixture was then diluted with ether, concentrated onto silica geland purified by flash chromatography with 5% ethyl acetate hexane aseluant giving 9.0 g (44%) of product as a white fluffy solid. ¹H NMR(CDCl₃), δ (ppm): 8.57 (s, 1H), 7.95 (d, 2H), 3.97 (s, 6H).

A suspension of 5-fluoro-isophthalic acid dimethyl ester (1.7 g, 8.0mmol) in methanol (41 ml) was treated with 1.0 N sodium hydroxide (7.2ml, 7.2 mmol). The reaction was left stirring overnight at roomtemperature. After the solution was concentrated, the residue wasdissolved in water and transferred to a separatory funnel. The aqueouslayer was washed with dichloromethane (3 times) and then acidified with1.0 N HCl to pH 2. Ethyl acetate was used to extract the precipitate,which was then washed with brine and dried over anhydrous sodiumsulphate. After removal of solvent in vacuo, a total of 1.3 g (83%) of5-fluoro-isophthalic acid monomethyl ester was isolated as a whitesolid. ¹H NMR (DMSO), δ (ppm): 8.31 (t, 1H), 7.96 (m, 2H), 3.91 (s, 3H).

Triethylamine (2.2 ml, 16.0 mmol) and isobutyl chloroformate (1.0 ml,8.0 mmol) were added to an ice-cooled solution of 5-fluoro-isophthalicacid monomethyl ester (1.3 g, 6.7 mmol) in dichloromethane (20 ml) andthen warmed to room temperature. After stirring for 2 h, the reactionmixture was filtered and concentrated. The residue was re-dissolvedtetrahydrofuran (10 ml) and then sodium borohydride (1.1 g, 29.02 mmol)in water (3 ml) was added drop-wise. After 1 h, the reaction wasquenched with methanol and then diluted with ethyl acetate, washed withwater and brine, dried over anhydrous sodium sulfate, filtered andconcentrated. Flash column chromatography on silica gel using 30% ethylacetate in hexanes afforded 667 mg (54%) of3-fluoro-5-hydroxymethyl-benzoic acid methyl ester as a colorless oil.¹H NMR (CDCl₃), δ (ppm): 7.82 (s, 1H), 7.63 (d, 1H), 7.32 (d, 1H), 4.76(s, 2H), 3.93 (s, 3H).

Ethanol (2 ml) was added to round bottom flask containing3-fluoro-5-hydroxymethyl-benzoic acid methyl ester (667 mg, 3.6 mmol)and palladium (10 wt. % on activated carbon, 300 mg) under argon. Theflask was evacuated using a water aspirator and then filled withhydrogen from a balloon. After stirring for 2 h, the palladium on carbonwas removed by filtration through celite. The filtrate was thenconcentrated to afford 520 mg (87%) of 3-fluoro-5-methyl-benzoic acidmethyl ester. ¹H NMR (CDCl₃), δ (ppm): 7.65 (s, 1H), 7.51 (d, 1H), 7.08(d, 1H), 3.91 (s, 3H), 2.40 (s, 3H).

0.5 N Lithium hydroxide (7.4 ml, 3.7 mmol) was added to a solution3-fluoro-5-methyl-benzoic acid methyl ester (520 mg, 3.1 mmol) intetrahydrofuran (7.4 ml). The reaction was stirred at 75° C. for 2 h andthen the solvent was removed in vacuo. The residue was dissolved in asmall amount of water and then acidified (pH about 2) by the addition of10% HCl (aq.). Following extraction of the aqueous layer with ethylacetate, the organic layer was then washed with water and saturatedbrine, dried over anhydrous sodium sulfate, filtered, and concentratedto afford 469 mg (98%) of 3-fluoro-5-methyl-benzoic acid as a whitesolid. 1H NMR (DMSO), d (ppm): 7.62 (s, 1H), 7.45 (d, 1H), 7.32 (d, 1H),2.38 (s, 3H).

Example 5 3-Methoxymethyl-benzoic acid

A mixture of 3-bromomethyl-benzoic acid methyl ester (556 mg, 2.4 mmol)and potassium carbonate (670 mg, 4.9 mmol) in methanol (10 ml) andtetrathydrofuran (10 ml) was heated at 55° C. for 2 h. After cooling,the reaction mixture was diluted with water and then extracted withethyl acetate. The organic layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, filtered and concentrated.After drying in vacuo, 3-methoxymethyl-benzoic acid methyl ester (436mg, quantitative) was isolated as a white solid. ¹H NMR (CDCl₃), δ(ppm): 8.01 (s, 1H), 7.98 (d, 1H), 7.55 (d, 1H), 7.43 (t, 1H), 4.50 (s,2H), 3.92 (s, 3H), 3.41 (s, 3H).

1 N Sodium hydroxide (3.6 ml, 3.6 mmol) was added to a3-methoxymethyl-benzoic acid methyl ester (436 mg, 2.4 mmol) in methanol(5 ml) and tetrahydrofuran (5 ml). The reaction was stirred at 70° C.for 30 min. and then the solvent was removed in vacuo. The residue wasdissolved in a small amount of water and then acidified (pH about 2) bythe addition of 1 N HCl (aq.). Following extraction of the aqueous layerwith ethyl acetate, the organic layer was then washed with water andsaturated brine, dried over anhydrous sodium sulfate, filtered, andconcentrated to afford 395 mg (98%) of 3-methoxymethyl-benzoic acid as awhite solid. ¹H NMR (DMSO), δ (ppm): 7.90 (s, 1H), 7.87 (d, 1H), 7.56(d, 1H), 7.48 (t, 1H), 4.48 (s, 2H), 3.31 (s, 3H).

Example 6 N-Hydroxy-3-methoxy-benzamidine

Using the general procedure of Shine et al., J. Heterocyclic Chem.(1989) 26:125-128, hydroxylamine hydrochloride (22 ml, 5 M, 110 mmol)and sodium hydroxide (11 ml, 10 M, 110 mmol) were added to a solution of3-methoxybenzonitrile (11.5 ml. 94 mmol) in ethanol (130 ml). Thereaction mixture was then heated at reflux (80° C.) for 12 h. After themixture was cooled, most of the solvent was removed in vacuo. The crudeproduct was partitioned between ethyl acetate and water, washed withsaturated brine, dried over anhydrous sodium sulfate and the solvent wasremoved in vacuo. Flash chromatography on silica gel using 35-50% ethylacetate in hexane yielded the title compound (8.05 g, 52%). Examples 7-9were prepared in an analogous method to the procedure given in Example6.

Example 7 N-Hydroxy-benzamidine

N-hydroxy-benzamidine (4.83 g, 91%, white solid) was obtained frombenzonitrile (4 g, 38.9 mmol), hydroxylamine hydrochloride (8.89 ml,44.0 mmol) and sodium hydroxide (4.49 ml, 45.0 mmol) in ethanol (30 ml).¹H NMR (CDCl₃), δ (ppm): 8.81 (broad peak, 1H), 7.63 (m, 2H), 7.39 (m,3H), 4.91 (s, 2H).

Example 8 N-Hydroxy-3-methyl-benzamidine

N-Hydroxy-3-methyl-benzamidine (3.65 g, 94%, white solid) was obtainedfrom m-tolunitrile (3 g, 26.0 mmol), hydroxylamine hydrochloride (5.9ml, 29.6 mmol), and sodium hydroxide (3.0 ml, 29.9 mmol) in ethanol (20ml). ¹H NMR (CDCl₃), δ (ppm): 8.25 (broad peak, 1H), 7.36 (m, 2H), 7.25(m, 2H), 4.88 (s, 2H), 2.38 (s, 3H).

Example 9 3-Cyano-N-hydroxy-benzamidine

3-Cyano-N-hydroxy-benzamidine (1.32 g, 52%, white solid) was obtainedfrom isophthalonitrile (2 g, 15.6 mmol), hydroxylamine hydrochloride(3.12 ml, 5 M, 15.6 mmol) and sodium hydroxide (15.6 ml, 1 M, 15.6 mmol)in ethanol (20 ml). Purification was performed by flash columnchromatography using 20-50% ethyl acetate in hexanes. ¹H NMR (DMSO), δ(ppm): 9.91 (s, 1H), 8.06 (s, 1H), 8.01 (d, 1H), 7.85 (d, 1H), 7.59 (t,1H), 6.01 (bs, 2H).

Example 10 5-Chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole

Chloroacetyl chloride (0.72 ml, 9.03 mmol) and triethylamine (1.50 ml,10.23 mmol) were added to N-hydroxy-3-methoxy-benzamidine (1 g, 6.02mmol) in dichloromethane (12.0 ml) at 0° C. and the resulting mixturewas stirred for 20 min. To effect cyclization to oxadiazole, thesolution was concentrated and DMF (20 ml) was added to the residue andheated at 120° C. for 5 h. The product was purified by flashchromatography using 10-20% ethyl acetate in hexane affording 0.90 g(66% yield over 2 steps) of the title compound (yellow oil). ¹H NMR(CDCl₃), δ (ppm): 7.68 (m, 1H), 7.60 (d, 1H), 7.40 (t, 1H), 7.07 (m,1H), 4.76 (s, 2H), 3.88 (s, 3H).

Examples 11-14 were prepared in an analogous method to the proceduregiven in Example 10.

Example 11 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole

5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole (1.62 g, 57% yield over 2steps, yellow oil) was obtained from chloroacetyl chloride (1.76 ml,22.05 mmol) and triethylamine (3.32 ml, 24.99 mmol) withN-hydroxy-benzamidine (2 g, 14.7 mmol) in dichloromethane (29.3 ml).Purification was performed by flash chromatography using 10% ethylacetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.08 (m, 2H), 7.51 (m, 3H),4.76 (s, 2H).

Example 12 5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole

5-Chloromethyl-3-m-tolyl-[1,2,4]oxadiazole (1.75 g, 62% yield over 2steps, yellow oil) was obtained from chloroacetyl chloride (1.59 ml,20.0 mmol) and triethylamine (3.00 ml, 22.7 mmol) withN-hydroxy-3-methyl-benzamidine (2 g, 13.3 mmol) in dichloromethane (26.6ml). Purification was performed by flash chromatography using 10% ethylacetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 7.90 (s, 1H), 7.87 (s, 1H),7.36 (m, 2H), 4.75 (s, 2H), 2.34 (s, 3H)

Example 13 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile

3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile (3.57 g, 43%) wasobtained from 2-chloro-N-hydroxy-acetamidine (4.05 g, 37.4 mmol) and3-cyanobenzoyl-chloride (6.2 g, 37.4 mmol) in dichloromethane (60 ml)with triethylamine (6.5 ml, 46.7 mmol). Purification was performed bysilica gel chromatography. ¹H NMR (CDCl₃), δ (ppm): 8.47 (bs, 1H), 8.41(dd, 1H), 7.91 (dd, 1H), 7.72 (t, 1H), 4.70 (s, 2H); GC-MS (M+): 219.

Example 14 3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile

3-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile (1.2 g, 87%, lightbrown solid): 3-cyano-N-hydroxy-benzamidine (1.0 g, 6.2 mmol),triethylamine (1.5 ml, 10.6 mmol) and chloroacetyl chloride (0.74 ml,9.3 mmol) in dichloromethane (12 ml). Purification was performed bydecolorizing with silica gel. 1H NMR (CDCl₃), d (ppm): 8.40 (s, 1H),8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).

Example 15 3-Chloromethyl-5-m-tolyl-[1,2,4]oxadiazole

3-Methyl-benzoyl chloride (0.80 ml, 6.1 mmol) was added to a solution of2-chloro-N-hydroxy-acetamidine (440 mg, 4.1 mmol) in dichloromethane (10ml) at room temperature and the resulting mixture was stirred for 30min. Then triethylamine (0.62 ml, 4.5 mmol) was added and the resultingmixture was stirred for 30 min. The product was partitioned intodichloromethane and the organic layer was washed with water and brineand dried over sodium sulfate. Evaporation of the solvent and flashchromatography on silica (10-20% ethyl acetate in hexanes) yielded theacyclic ester intermediate (814 mg). A solution of this intermediate inDMF (10 ml) was heated at 135° C. for 4 h. The product was partitionedinto ethyl acetate and the organic layer was washed with water and brineand dried over sodium sulfate. Evaporation of the solvent and flashchromatography on silica (5% ethyl acetate in hexanes) yielded3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (469 mg, 54% over 2 steps,white solid). ¹H NMR (CDCl₃), δ (ppm): 7.99 (s, 1H), 7.97 (m, 1H), 7.43(d, 2H), 4.68 (s, 2H), 2.45 (s, 3H).

Example 16 3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole

DMF (10 ml) was added to a mixture of 3-fluorobenzoic acid (710 mg, 5.07mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI) (972 mg, 5.07 mmol), 1-hydroxybenzotriazole hydrate (HOBt) (685mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) atroom temperature and then stirred overnight. The reaction mixture wasdiluted with ethyl acetate, washed with water (3 times) and brine, driedover anhydrous sodium sulfate, filtered and concentrated. DMF (14 ml)was added to the residue and the resulting solution was heated at 135°C. for 3.5 h to effect cyclization to oxadiazole. After cooling thereaction mixture was washed with water (3 times) and brine, dried overanhydrous sodium sulfate, filtered and concentrated.3-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (383 mg, 35% yieldover 2 steps, yellow oil) was obtained by flash chromatography on silicagel, using 5% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 7.96 (d,1H), 7.86 (m, 1H), 7.54 (m, 1H), 7.33 (m, 1H), 4.68 (s, 2H).

Examples 17-30 were prepared in an analogous method to the proceduregiven in Example 16.

Example 17 3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole

3-Chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (197 mg, 20% yield over2 steps, white solid) was obtained from 3-thiophenecarboxylic acid (700mg, 4.96 mmol), EDCI (950 mg, 4.96 mmol), HOBt (670 mg, 4.96 mmol) and2-chloro-N-hydroxy-acetamidine (538 mg, 5.46 mmol) in DMF (10 ml). Theacyclic product was purified by flash column chromatography eluting with2:1.2:0.8 dichloromethane:hexane:ethyl acetate. The title compound waspurified by flash column chromatography using 5% ethyl acetate inhexane. ¹H NMR (CDCl₃), δ (ppm): 8.28 (s, 1H), 7.70 (d, 1H), 7.48 (m,1H).

Example 18 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine

3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine (25 mg, 4%yield over 2 steps) was obtained from 5-methynicotinic acid (472 mg,3.44 mmol), EDCI (652 mg, 3.44 mmol), HOBt (465 mg, 3.44 mmol) and2-chloro-N-hydroxy-acetamidine (340 mg, 3.13 mmol) in DMF (10 ml). Theacyclic intermediate was purified by flash column chromatography using100% ethyl acetate; 200 mg (30%) of the acyclic ester was also isolatedas side product.

Example 19 3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole (335 mg, 30% yieldover 2 steps, yellow solid) was obtained from 3-nitrobenzoic acid (847mg, 5.07 mmol), EDCI (972 mg, 5.07 mmol), HOBt (685 mg, 5.07 mmol) and2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) in DMF (10 ml). Theacyclic intermediate was purified by flash column chromatography using100% ethyl acetate. Purification was performed by flash columnchromatography using 15% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 9.03 (t, 1H), 8.50 (t, 2H), 7.79 (t, 1H), 4.71 (s, 2H)

Example 20 4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine

4-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine (316 mg, 28%yield over 2 steps, yellow oil) was obtained from6-methylpyridine-4-carboxylic acid (800 mg, 5.8 mmol), EDCI (1.12 g, 5.8mmol), HOBt (788 mg, 5.8 mmol) and 2-chloro-N-hydroxy-acetamidine (575mg, 5.3 mmol) in DMF (10 ml) plus triethylamine (536 mg, 5.3 mmol).Purification was performed by flash column chromatography using 30%ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.75 (d, 1H), 7.88 (s,1H), 7.79 (d, 1H), 4.70 (s, 2H), 2.70 (s, 3H)

Example 21 3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole (446 mg, 52% yieldover 2 steps, yellow oil) was obtained from 3-ethylbenzoic acid (770 mg,3.81 mmol), EDCI (803 mg, 4.19 mmol), HOBt (566 mg, 4.19 mmol) and2-chloro-N-hydroxy-acetamidine (454 mg, 4.19 mmol) in DMF (10 ml).Purification was performed by flash column chromatography using 5% ethylacetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 7.96 (t, 2H), 7.42 (m, 2H),4.68 (s, 2H), 2.74 (m, 2H), 1.28 (m, 3H).

Example 223-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine

3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine (40 mg,4% yield over 2 steps, yellow solid) was obtained from3-(dimethylamino)benzoic acid (656 mg, 3.97 mmol), EDCI (761 mg, 3.97mmol), HOBt (536 mg, 3.97 mmol) and 2-chloro-N-hydroxy-acetamidine (500mg, 3.6 mmol) in DMF (10 ml). Purification was performed by flash columnchromatography using 5% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 7.46 (t, 2H), 7.37 (t, 1H), 6.94 (d, 1H), 4.68 (s, 2H), 3.04 (s,6H).

Example 23 3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (406 mg, 43% yieldover 2 steps, white solid) was obtained from 3-chlorobenzoic acid (708mg, 4.52 mmol), EDCI (866 mg, 4.52 mmol), HOBt (611 mg, 4.52 mmol) and2-chloro-N-hydroxy-acetamidine (446 mg, 4.11 mmol) in DMF (10 ml).Purification was performed by flash column chromatography using 5% ethylacetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.17 (t, 1H), 8.05 (d, 1H),7.59 (t, 1H), 7.50 (t, 1H), 4.68 (s, 2H).

Example 243-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole (707 mg,55% yield over 2 steps, light yellow oil) was obtained from3-trifluoromethoxybenzoic acid (1.05 g, 5.07 mmol), EDCI (972 mg, 5.07mmol), HOBt (685 mg, 5.07 mmol) and 2-chloro-N-hydroxy-acetamidine (500mg, 4.61 mmol) in DMF (10 ml). Purification was performed by flashcolumn chromatography using 5% ethyl acetate in hexane. ¹H NMR (CDCl₃),δ (ppm): 8.10 (m, 1H), 8.03 (s, 1H), 7.61 (t, 1H), 7.48 (d, 1H), 4.69(s, 2H).

Example 25 5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole

5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole (707 mg, 55% yieldover 2 steps, white solid) was obtained from 3-bromobenzoic acid (1.05g, 5.07 mmol), EDCI (972 mg, 5.07 mmol), HOBt (685 mg, 5.07 mmol) and2-chloro-N-hydroxy-acetamidine (500 mg, 4.61 mmol) in DMF (10 ml).Purification was performed by flash column chromatography using 5% ethylacetate in hexane. 1H NMR (CDCl₃) d (ppm): 8.10 (m, 1H), 8.03 (s, 1H),7.61 (t, 1H), 7.48 (d, 1H), 4.69 (s, 2H).

Example 26 3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole

3-Chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (202 mg, 20%, off-whitesolid) was obtained from thiophene-2-carboxylic acid (649 mg, 5.1 mmol),2-chloro-N-hydroxy-acetamidine (500 mg, 4.6 mmol), EDCI (972 mg, 5.1mmol) and HOBt (684 mg, 5.1 mmol) in DMF (5 ml). Purification wasperformed by SPE (flash) chromatography using 5% ethyl acetate inhexanes. ¹H NMR (CDCl₃), δ (ppm): 8.00 (s, 1H), 7.83 (d, 1H), 7.19 (t,1H), 4.13 (s, 2H).

Example 27 3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole (312 mg,46%, colorless oil) was obtained from 3-fluoro-5-methyl-benzoic acid(469 mg, 3.0 mmol), 2-chloro-N-hydroxy-acetamidine (363 mg, 3.3 mmol),EDCI (641 mg, 3.3 mmol) and HOBt (452 mg, 3.3 mmol) in DMF (5 ml).Purification was performed by SPE (flash) chromatography using 5% ethylacetate in hexanes. ¹H NMR (CDCl₃), δ (ppm): 7.79 (s, 1H), 7.65 (d, 1H),7.15 (d, 1H), 4.67 (s, 2H), 2.46 (s, 3H).

Example 28 3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole

3-Chloromethyl-5-thiazol-4-yl-[1,2,4]oxadiazole (37 mg, 5%, yellowsolid) was obtained from thiazole-4-carboxylic acid (500 mg, 3.9 mmol),2-chloro-N-hydroxy-acetamidine (462 mg, 4.3 mmol), EDCI (817 mg, 4.3mmol) and HOBt (575 mg, 4.3 mmol) in DMF (5 ml). Purification wasperformed by SPE (flash) chromatography using 30% ethyl acetate inhexanes. ¹H NMR (CDCl₃), δ (ppm): 9.02 (d, 1H), 8.42 (d, 1H), 4.70 (s,2H).

Example 29 3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole (2.9 g, 44%, whitesolid) was obtained from 3-iodo-benzoic acid (5.0 g, 20.2 mmol),2-chloro-N-hydroxy-acetamidine (2.4 g, 22.2 mmol), EDCI (4.3 g, 22.2mmol) and HOBt (3.0 g, 22.2 mmol) in DMF (10 ml). The acyclic esterintermediate was purified by flash column chromatography using 50-80%ethyl acetate in hexanes. The title compound was purified by SPE (flash)chromatography using 5% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ(ppm): 8.52 (s, 1H), 8.13 (d, 1H), 7.96 (d, 1H), 7.29 (t, 1H), 4.68 (s,2H).

Example 30 3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole

3-Chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole (193 mg,34%, light yellow oil) was obtained from 3-methoxymethyl-benzoic acid(395 mg, 2.4 mmol), 2-chloro-N-hydroxy-acetamidine (284 mg, 2.6 mmol),EDCI (501 mg, 2.6 mmol) and HOBt (353 mg, 2.6 mmol) in DMF (5 ml).Purification was performed by SPE (flash) chromatography using 5% ethylacetate in hexanes. ¹H NMR (CDCl₃), δ (ppm): 8.14 (s, 1H), 8.08 (d, 1H),7.61 (d, 1H), 7.53 (t, 1H), 4.68 (s, 2H), 4.54 (s, 2H), 3.44 (s, 3H).

Example 31 5-Furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol

2-Furoyl chloride (0.76 ml, 7.66 mmol) was added in a dropwise manner toa solution of 4-methyl-3-thiosemicarbazide (732 mg, 6.96 mmol) andpyridine (7 ml) and the resulting solution was stirred at roomtemperature for 4 h. The reaction mixture was diluted with ethyl acetate(100 ml), successively washed with water (3×100 ml) and brine (100 ml).The organic phase was dried (sodium sulfate), filtered and concentratedin-vacuo. The residue was suspended in sodium bicarbonate (70 ml, 69.6mmol, 1 M water) and left stirring at 100° C. overnight. The reactionmixture was cooled to 0° C., then brought to pH about 6 usinghydrochloric acid (70 ml, 1 N water). The title compound (298 mg) wascollected by filtration as a white solid. ¹H NMR (CDCl₃), δ (ppm): 11.4(bs, 1H), 7.63 (d, 1H), 7.02 (d, 1H), 6.60 (dd, 1H), 3.83 (s, 3H).

Examples 32-35 were prepared in an analogous method to the proceduregiven in Example 31.

Example 32 4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol

4-Methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol (478 mg, off-white solid)was obtained from 4-methyl-3-thiosemicarbazide (732 mg, 6.96 mmol) andpyridine (7 ml) with benzoyl chloride (0.89 ml, 7.66 mmol). Then sodiumbicarbonate (70 ml, 69.6 mmol, 1 M water) was added at 100° C. overnightand the title compound was collected by filtration. ¹H NMR (CDCl₃), δ(ppm): 12.3 (bs, 1H), 7.55 (m, 5H), 3.65 (s, 3H).

Example 33 4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol

4-Methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol (44 mg, greenishsolid) was obtained from 4-methyl-3-thiosemicarbazide (537 mg, 5.11mmol) and pyridine (7 ml) with 2-pyridinecarbonyl chloride hydrochloride(1.00 g, 5.62 mmol). Then sodium bicarbonate (51 ml, 1 M water) wasadded at 100° C. overnight and the title compound was collected usingextraction and evaporation. ¹H NMR (CDCl₃), δ (ppm): 11.1 (bs, 1H), 8.70(d, 1H), 8.02 (d, 1H), 7.84 (m, 1H), 7.41 (dd, 1H), 4.05 (s, 3H).

Example 345-(4-Benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol

(83.3 mg, dirty yellow solid) was obtained from4-methyl-3-thiosemicarbazide (346 mg, 3.29 mmol) and pyridine (7 ml)with 4-benzyl-2-morpholinecarbonyl chloride hydrochloride (1.00 g, 3.62mmol). Then sodium bicarbonate (33 ml, 1 M water) was added at 100° C.overnight and the title compound was collected using extraction andevaporation. ¹H NMR (CDCl₃), δ (ppm): 9.48 (bs, 1H), 7.25 (m, 5H), 4.68(dd, 1H), 3.86 (dAb, 1H), 3.68 (tAB, 1H), 3.59-3.64 (m, 5H), 3.07 (d,1H), 2.88 (d, 1H), 2.61 (t, 1H), 2.37 (dt, 1H).

Example 35 5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol

5-tert-Butyl-4-methyl-4H-[1,2,4]triazole-3-thiol (2.21 g, 83%, off-whitesolid) was obtained from 4-methyl-3-thiosemicarbazide (1.80 g, 17.2mmol) and pyridine (20 ml) with trimethylacetyl chloride (1.92 ml, 15.6mmol). Then sodium hydroxide (200 ml, 5% water) was added and leftstirring at 60° C. overnight and the title compound was collectedextraction and evaporation. ¹H NMR (CDCl₃), δ (ppm): 11.7 (bs, 1H), 3.72(s, 3H) 1.40 (s, 9H).

Example 36 4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol

A solution of 4-methyl-3-thiosemicarbazide (902 mg, 8.58 mmol),nicotinic acid (960 mg, 7.80), EDCI (1.64 g, 8.58 mmol), HOBt (1.16 g,8.58 mmol) in DMF (10 ml) was stirred at room temperature overnight. Thereaction mixture was diluted with ethyl acetate (100 ml), successivelywashed with hydrochloric acid (50 ml, 10% aqueous), water (50 ml),saturated sodium carbonate (50 ml, aqueous), water (50 ml) and brine (50ml). The organic phase was dried (sodium sulfate), filtered andconcentrated in-vacuo. The residue was stirred in sodium hydroxide (53.4ml, 66.7 mmol, 5% aqueous) at 60° C. overnight. The reaction mixture wascooled to room temperature, then carefully brought to pH about 6 usinghydrochloric acid (1 N water). The aqueous phase was saturated withsolid sodium chloride, then extracted with ethyl acetate (4×50 ml). Thecombined organic phase was washed with brine (100 ml), dried (sodiumsulfate), filtered and concentrated in-vacuo (180 mg, off-white solid).¹H NMR (CDCl₃), δ (ppm): 11.6 (bs, 1H), 8.94 (s, 1H), 8.83 (dd, 1H),7.98 (m, 1H), 7.51 (dd, 1H), 3.69 (s, 3H).

Examples 37-39 were prepared in an analogous method to the proceduregiven in Example 36.

Example 37 4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol

4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (693 mg, whitesolid) was obtained from 4-methyl-3-thiosemicarbazide (902 mg, 8.58mmol), 3-thiophenecarboxylic acid (1 g, 7.80 mmol), EDCI (1.64 g, 8.58mmol), HOBt (1.16 g, 8.58 mmol) in DMF (10 ml). Then sodium hydroxide(88 ml, 110 mmol, 5% aqueous) at 60° C. overnight and the title compoundwas product collected extraction and evaporation. ¹H NMR (CDCl₃), δ(ppm): 11.4 (bs, 1H), 7.77 (dd, 1H), 7.51 (dd, 1H), 7.42 (dd, 1H), 3.61(s, 3H).

Example 38 4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol

4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol (71.2 mg, stickyyellow oil) was obtained from 4-methyl-3-thiosemicarbazide (902 mg, 8.58mmol), 4-carboxythiazole (1.01 g, 7.80), EDCI (1.64 g, 8.58 mmol), HOBt(1.16 g, 8.58 mmol) in DMF (10 ml). Then sodium hydroxide (43 ml, 54mmol, 5% aqueous) at 60° C. overnight and the title compound wascollected extraction and evaporation.

Example 39 5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol

5-Cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol (403 mg, beige solid)was obtained from 4-methyl-3-thiosemicarbazide (1.80 g, 17.2 mmol),cyclohexane carboxylic acid (2 g, 15.6 mmol), EDCI (2.99 g, 17.2 mmol)and HOBt (2.10 g, 17.2 mmol) in DMF (20 ml); then sodium hydroxide (195ml, 244 mmol, 5% aqueous) at 60° C. overnight.

Example 402-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole

1H-Benzoimidazole-2-thiol (150 mg, 1 mmol) was added to a solution ofthe 3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (30 mg, 0.13mmol) and potassium carbonate (50 mg, 0.36 mmol) in DMF (2 ml) at roomtemperature. The solvent was removed in vacuo and the product obtainedby flash chromatography using 20-100% ethyl acetate in hexane. ¹H NMR(CDCl₃), δ (ppm): 7.71 (d, 1H), 7.62 (d, 1H), 7.53 (m, 2H), 7.42 (t,1H), 7.18 (overlapping, m, 3H), 4.52 (s, 2H), 3.87 (s, 3H).

Examples 41-92 were prepared in an analogous method to the proceduregiven in Example 40.

Example 415-(3-Methoxy-phenyl)-3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

The title compound was prepared from3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50 mg, 0.22mmol), potassium carbonate (92.4 mg, 0.67 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 30-40% ethyl acetate in hexanesafforded 76 mg (90%) of the title compound as a white solid. ¹H NMR(CDCl₃), δ (ppm): 7.68 (d, 1H), 7.57 (t, 1H), 7.49 (m, 2H), 7.41 (t,1H), 7.15 (m, 2H), 4.53 (s, 2H), 3.85 (s, 3H), 3.72 (s, 3H). LC-MS(M+1)⁺ 386.3.

Example 423-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-benzonitrile

3-[5-(1-Methyl-5-thiophen-2-yl-1H-imidazol-2-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-benzonitrile(39 mg, 47%, white solid) was obtained from3-chloromethyl-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-benzonitrile (50mg, 0.22 mmol), potassium carbonate (92.4 mg, 0.67 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.8 mg, 0.27 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 50-70% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 8.34 (s, 1H), 8.28 (d, 1H), 7.79 (d, 1H), 7.60 (t,1H), 7.53 (d, 1H), 7.49 (d, 1H), 7.19 (m, 1H), 4.70 (s, 2H), 3.74 (s,3H). LS-MS (ES+full scan, C₁₇H₁₂N₆OS₂) M⁺ calc. 380.05, found (M+1)⁺381.04.

Example 433-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-phenyl-[1,2,4]oxadiazole(41.2 mg, 44%, off-white solid) was obtained from3-chloromethyl-5-phenyl-[1,2,4]oxadiazole (50 mg, 0.26 mmol), potassiumcarbonate (106 mg, 0.77 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (60.8 mg, 0.31 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 50% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ(ppm): 8.09 (m, 2H), 7.57 (m, 5H), 7.17 (dd, 1H), 4.53 (s, 2H), 3.72 (s,3H).

Example 442-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-1H-benzoimidazole

2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-methyl-1H-benzoimidazole(75.5 mg, 70.5%, white foam) was obtained from3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (82 mg, 0.365mmol), potassium carbonate (210 mg, 1.520 mmol),2-thiol-5-methyl-1H-benzoimidazole (50 mg, 0.305 mmol) in acetonitrile(3 ml) at room temperature. Purification was performed by SPE flashchromatography using 50% ethyl acetate in hexanes followed bytrituration with ethyl acetate. ¹H NMR (CDCl₃), δ (ppm): 11.95 (bs, 1H),7.80 (d, 1H), 7.70 (s, 1H), 7.52 (m, 2H), 7.21 (dd, 2H), 7.17 (d, 1H),4.40 (s, 2H), 3.95 (s, 3H), 2.50 (s, 3H).

Example 453-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(76 mg, 85%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99.4 mg, 0.72 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (56.7 mg, 0.27 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 50-70% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 7.89 (m, 2H), 7.50 (m, 2H), 7.40 (m, 2H), 7.18 (t,1H), 4.52 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H).

Example 463-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole(84 mg, 86%, white solid) was obtained from3-chloromethyl-5-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazole (60 mg,0.23 mmol), potassium carbonate (95 mg, 0.69 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (54 mg, 0.27 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 40-60% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 8.38 (s, 1H), 7.29 (d, 1H), 7.86 (d, 1H), 7.68 (t,1H), 7.50 (t, 2H), 7.19 (m, 1H), 4.57 (s, 2H), 3.75 (s, 3H).

Example 473-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

3-(3-Methoxy-phenyl)-5-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(74.3 mg, 88%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (53.3 mg, 0.27mmol), 5-chloromethyl-3-(3-methoxy-phenyl)-[1,2,4]oxadiazole (50 mg,0.22) mmol), and potassium carbonate (92.6 mg, 0.67 mmol) inacetonitrile (1 ml) at room temperature. Purification was performed bySPE (flash) chromatography using 40-70% ethyl acetate in hexane. ¹H NMR(CDCl₃), δ (ppm): 7.62 (d, 1H), 7.52 (d, 2H), 7.48 (d, 1H), 7.37 (t,1H), 7.18 (t, 1H), 7.06 (m, 1H), 4.64 (s, 2H), 3.84 (s, 3H), 3.71 (s,3H). LC-MS (MH+): 386.06.

Example 485-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole

5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole(79.9 mg, 87%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (86.8 mg, 0.44mmol), 5-chloromethyl-3-phenyl-[1,2,4]oxadiazole (50 mg, 0.26 mmol), andpotassium carbonate (152.0 mg, 1.1 mmol) in acetonitrile (1 ml) at roomtemperature. Purification was performed by SPE (flash) chromatographyusing 40-70% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.02 (d,2H), 7.47 (m, 5H), 7.18 (t, 1H).

Example 495-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl-[1,2,4]oxadiazole

5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-m-tolyl-[1,2,4]oxadiazole(71.8 mg, 91%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (78.9 mg, 0.40mmol), 5-chloromethyl-3-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol) andpotassium carbonate (138.2 mg, 1.0 mmol) in acetonitrile (1 ml) at roomtemperature. Purification was performed by SPE (flash) chromatographyusing 45-65% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 7.82 (d,2H), 7.52 (d, 1H), 7.47 (d, 1H), 7.31 (m, 2H), 7.18 (m, 1H), 4.64 (s,2H), 3.70 (s, 3H), 2.39 (s, 3H). LC-MS (MH⁺): 370.06.

Example 503-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile

3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-benzonitrile(130 mg, 75%) was obtained from3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile (100 mg, 0.45mmol) with K₂CO₃ (189 mg, 1.36 mmol) and 4-methyl-5-(2-thienyl)1,2,4-triazole-3-thiol (110 mg, 0.54 mmol) in acetonitrile at roomtemperature. Purification was performed by flash chromatography using50% ethyl acetate in dichloromethane. ¹H NMR (CDCl₃), δ (ppm): 8.38 (bs,1H), 8.32 (d, 1H), 7.88 (d, 1H), 7.68 (t, 1H), 7.51 (dd, 2H), 7.18 (dd,1H), 4.56 (s, 2H), 3.75 (s, 3H); LC-MS (M+H)⁺: 381.

Example 513-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[4-Methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole(82.8 mg, 90%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),4-methyl-5-(2-methyl-thiazol-4-yl)-4H-[1,2,4]triazole-3-thiol (61 mg,0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 80% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 7.96 (s, 1H), 7.88 (m, 2H), 7.38 (m, 2H), 4.53 (s,2H), 3.91 (s, 3H), 2.75 (s, 3H), 2.41 (s, 3H).

Example 523-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[5-(2-Methyl-thiazol-4-yl)-[1,3,4]oxadiazol-2-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole(89 mg, 99%, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),5-(2-methyl-thiazol-4-yl)-[1,3,4]oxadiazole-2-thiol (57.3 mg, 0.29 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 80% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ(ppm): 7.97 (s, 1H), 7.90 (m, 2H), 7.40 (m, 2H), 4.66 (s, 2H), 2.80 (s,3H), 2.42 (s, 3H).

Example 533-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-2-yl-[1,2,4]oxadiazole(80 mg, 88%, white solid) was obtained from3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (50 mg, 0.25 mmol),potassium carbonate (103 mg, 0.75 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (59 mg, 0.30 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 50-70% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 7.89 (d, 1H), 7.65 (m, 1H), 7.51 (m, 2H), 7.19 (m,2H), 4.50 (t, 2H), 3.74 (s, 3H).

Example 543-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[5-(2,4-Dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole(54.2 mg, 57%, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),5-(2,4-dimethyl-thiazol-5-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (65.1mg, 0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purificationwas performed on silica gel using 80% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 7.88 (m, 2H), 7.39 (m, 2H), 4.57 (s, 2H), 3.49 (s,3H), 2.73 (s, 3H), 2.43 (d, 6H).

Example 553-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[4-Methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]oxadiazole(77.9 mg, 81%, yellow solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),4-methyl-5-(5-nitro-furan-2-yl)-4H-[1,2,4]triazole-3-thiol (65.1 mg,0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 80% ethyl acetate in. ¹H NMR (CDCl₃), δ(ppm): 7.90 (m, 2H), 7.46 (d, 1H), 7.40 (m, 2H), 7.33 (d, 1H), 4.59 (s,2H), 3.91 (s, 3H), 2.42 (s, 3H).

Example 564-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

4-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(66 mg, 75%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (55.3 mg, 0.29 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 80% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ(ppm): 8.79 (dd, 2H), 7.89 (m, 2H), 7.63 (dd, 2H), 7.40 (m, 2H), 4.59(s, 2H), 3.69 (s, 3H), 2.41 (s, 3H).

Example 573-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]-oxadiazole

3-[5-(4-tert-Butyl-phenyl)-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-5-m-tolyl-[1,2,4]-oxadiazole(100 mg, 99%, white waxy solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),5-(4-tert-butyl-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol (71.1 mg,0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 80% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 7.89 (m, 2H), 7.57 (m, 4H), 7.39 (d, 2H), 4.55 (s,2H), 3.61 (s, 3H), 2.40 (s, 3H), 1.35 (s, 9H).

Example 582-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

2-Chloro-5-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(53.8 mg, 56%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (99 mg, 0.72 mmol),5-(6-chloro-pyridin-3-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (65.2 mg,0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 80% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 8.67 (d, 1H), 8.02 (dd, 1H), 7.88 (m, 2H), 7.49 (d,1H), 7.40 (m, 2H), 4.58 (s, 2H), 3.65 (s, 3H), 2.42 (s, 3H).

Example 592-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole

2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-benzooxazole(138 mg, 62%) was obtained from3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (225.9 mg, 1.1mmol), benzooxazole-2-thiol (167 mg, 1.00 mmol), potassium carbonate(180 mg, 1.3 mmol) in DMF (4.5 ml) at room temperature overnight.Purification was performed on silica gel using 10-20% ethyl acetate inhexanes. ¹H NMR (CDCl₃), δ (ppm): 7.67 (d, 1H), 7.57 (m, 3H), 7.43 (t,1H), 7.21 (m, 2H), 7.14 (m, 1H), 4.50 (s, 2H), 3.86 (s, 3H).

Example 603-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiophen-3-yl-[1,2,4]oxadiazole(73.6 mg, 73%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (61 mg, 0.31 mmol),3-chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (50 mg, 0.28 mmol), andpotassium carbonate (15 mg, 0.83 mmol) in acetonitrile (1 ml) at roomtemperature. Purification was performed by SPE (flash) chromatographyusing 50-70% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.20 (d,1H), 7.64 (d, 1H), 7.48 (m, 3H), 7.18 (m, 1H), 4.52 (s, 2H), 3.72 (s,3H)

Example 613-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(5-Furan-2-yl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(51.0 mg, 76%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40.0 mg, 0.19 mmol),potassium carbonate (79 mg, 0.58 mmol),5-furan-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol (41.7 mg, 0.23 mmol) inacetonitrile (2 ml) at 60° C. overnight. Purification was performed onsilica gel using 80% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ (ppm):7.88 (m, 2H), 7.58 (s, 1H), 7.40 (m, 2H), 7.10 (d, 1H), 6.58 (dd, 1H),4.51 (s, 2H), 3.77 (s, 3H), 2.41 (s, 3H).

Example 625-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Fluoro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(75.4 mg, 83%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (51 mg, 0.26 mmol),3-chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole (50 mg, 0.24 mmol)and potassium carbonate (98 mg, 0.71 mmol) in acetonitrile (1 ml) atroom temperature. Purification was performed by SPE (flash)chromatography using 55-60% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 7.89 (d, 1H), 7.78 (m, 1H), 7.51 (m, 3H), 7.32 (m, 1H), 7.18 (m,1H), 4.55 (s, 2H), 3.74 (s, 3H)

Example 63 2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine

2-(5-m-Tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-pyridine (27.3 mg,96.5%) was obtained from 3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole(20.8 mg, 0.1 mmol) with pyridine-2-thiol (12.2 mg, 0.11 mmol) andpotassium carbonate in DMF (0.8 ml) at room temperature for 15 h.Purification was performed by flash chromatography on silica gel using20% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ (ppm): 8.47 (dd, 1H),7.94 (s, 1H), 7.90 (t, 1H), 7.51 (dt, 1H), 7.38 (d, 2H), 7.26 (dd, 1H),7.02 (dd, 1H), 4.61 (s, 2H), 2.42 (s, 3H).

Example 642-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]1-H-imidazo[4,5-b]pyridine

2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-imidazo[4,5-b]pyridine(74.5 mg, 96%) was obtained from3-chloromethyl-5-(3-methoxy-phenyl)-[1,2,4]oxadiazole (51.2 mg, 0.25mmol), 1H-imidazo[4,5-b]pyridine-2-thiol (37.5 mg, 0.23 mmol) andpotassium carbonate (80 mg, 0.58 mmol) in DMF (1.5 ml) at roomtemperature overnight. Purification was performed on silica gel using25-50% ethyl acetate in dichloromethane. ¹H-NMR (DMSO-d₆), δ (ppm): 8.24(br s, 1H), 7.88 br s, 1H), 7.66 (d, 1H), 7.55 (m, 3H), 7.29 (d, 1H),7.19 (m, 1H), 4.82 (s, 2H), 3.85 (s, 3H).

Example 655-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Fluoro-5-methyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(58 mg, 68%, white solid) was obtained from3-chloromethyl-5-(3-fluoro-5-methyl-phenyl)-[1,2,4]oxadiazole (50 mg,0.22 mmol), potassium carbonate (91.5 mg, 0.66 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (52.2 mg, 0.26 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 40-100% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 7.70 (s, 1H), 7.58 (d, 1H), 7.52 (m, 1H), 7.49 (m,1H), 7.18 (m, 1H), 7.12 (d, 1H), 4.53 (s, 2H), 3.73 (s, 3H), 2.42 (s,3H).

Example 663-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine

3-Methyl-5-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine(19.0 mg, 43%, light yellow solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (26 mg, 0.13 mmol),3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-5-methyl-pyridine (25 mg, 0.12mmol) and potassium carbonate (50 mg, 0.36 mmol) in acetonitrile (1 ml)at room temperature. Purification was performed by SPE (flash)chromatography using 100% ethyl acetate. ¹H NMR (CDCl₃), δ (ppm): 9.13(s, 1H), 8.65 (s, 1H), 8.16 (s, 1H), 7.50 (m, 2H), 7.19 (t, 1H) 4.57 (s,2H), 3.74 (s, 3H), 2.43 (s, 3H)

Example 673-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-phenyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(55.8 mg, 67%, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (48.4 mg, 0.23 mmol),potassium carbonate (96 mg, 0.70 mmol),4-methyl-5-phenyl-4H-[1,2,4]triazole-3-thiol (44.4 mg, 0.23 mmol) inacetonitrile (2 ml) at 60° C. overnight. Purification was performed onsilica gel using 50% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ (ppm):7.89 (m, 2H), 7.64 (m, 2H), 7.50 (m, 3H), 7.39 (m, 2H), 4.56 (s, 2H),3.61 (s, 3H), 2.41 (s, 3H).

Example 682-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

2-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(42.8 mg, 51%, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (48.4 mg, 0.23 mmol),potassium carbonate (96 mg, 0.70 mmol),4-methyl-5-pyridin-2-yl-4H-[1,2,4]triazole-3-thiol (44.6 mg, 0.23 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 50% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ(ppm): 8.62 (d, 1H), 8.30 (d, 1H), 7.85 (m, 3H), 7.36 (m, 3H), 4.59 (s,2H), 4.02 (s, 3H), 2.40 (s, 3H).

Example 694-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-morpholine

4-Benzyl-2-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-morpholine(95.8 mg, 83%, clear oil) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (59.9 mg, 0.29 mmol),potassium carbonate (119 mg, 0.86 mmol),5-(4-benzyl-morpholin-2-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (83.3mg, 0.29 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purificationwas performed on silica gel using 10% methanol in ethyl acetate. ¹H NMR(CDCl₃), δ (ppm): 7.88 (m, 2H), 7.31 (m, 7H), 4.75 (dd, 1H), 4.47 (dd,2H), 3.84 (m, 2H), 3.59 (bs, 5H), 3.20 (d, 1H), 2.72 (m, 2H), 2.43 (s,3H), 2.30 (dt, 1H).

Example 704-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

4-[4-Methyl-5-(5-thiophen-3-yl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(24 mg, 34%, white solid) was obtained from3-chloromethyl-5-thiophen-3-yl-[1,2,4]oxadiazole (40 mg, 0.20 mmol),potassium carbonate (82.5 mg, 0.60 mmol),4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (38.3 mg, 0.20 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 10% methanol in ethyl acetate. ¹H NMR (CDCl₃), δ(ppm): 8.80 (bs, 2H), 8.20 (dd, 1H), 7.62 (m, 3H), 7.45 (dd, 1H), 4.59(s, 2H), 3.70 (s, 3H).

Example 713-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-thiazol-4-yl-[1,2,4]oxadiazole(44 mg, 67%, white solid) was obtained from3-chloromethyl-5-thiophen-2-yl-[1,2,4]oxadiazole (37 mg, 0.18 mmol),potassium carbonate (75.3 mg, 0.54 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (43 mg, 0.22 mmol)in acetonitrile (1 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 50-100% ethyl acetate in hexanes. ¹HNMR (DMSO), δ (ppm): 9.37 (d, 1H), 8.86 (d, 1H), 7.80 (d, 1H), 7.65 (d,1H), 7.26 (t, 1H), 4.54 (s, 2H), 3.75 (s, 3H).

Example 723-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-nitro-phenyl)-[1,2,4]oxadiazole(21.1 mg, 13%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (91 mg, 0.46 mmol),3-chloromethyl-5-(3-nitro-phenyl)-[1,2,4]oxadiazole (100 mg, 0.42 mmol)and potassium carbonate (173 mg, 1.25 mmol) in acetonitrile (2 ml) atroom temperature. Purification was performed by SPE (flash)chromatography using 60% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 8.96 (s, 1H), 8.44 (t, 2H), 7.75 (t, 1H), 7.51 (m, 2H), 7.19 (t,1H), 4.59 (s, 2H), 3.76 (s, 3H)

Example 732-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine

2-Methyl-4-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine(59.2 mg, 66%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (51 mg, 0.26 mmol),4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine (50 mg, 0.24mmol), and potassium carbonate (100 mg, 0.72 mmol) in acetonitrile (1ml) at room temperature. Purification was performed by SPE (flash)chromatography using 100% ethyl acetate. ¹H NMR (CDCl₃), δ (ppm): 8.71(d, 1H), 7.79 (s, 1H), 7.73 (d, 1H), 7.49 (m, 2H), 7.19 (t, 1H), 4.58(s, 2H), 3.73 (s, 3H), 2.65 (s, 3H)

Example 743-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

3-[4-Methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(30 mg, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (100 mg, 0.72 mmol),4-methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol (46.1 mg, 0.24 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 5% methanol in ethyl acetate. ¹H NMR (CDCl₃), δ(ppm): 8.90 (bs, 1H), 8.76 (bs, 1H), 8.03 (m, 1H), 7.88 (m, 2H), 7.46(dd, 1H), 7.40 (m, 2H), 4.58 (s, 2H), 3.66 (s, 3H), 2.42 (s, 3H).

Example 753-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(60 mg, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (100 mg, 0.72 mmol),4-methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (47.3 mg, 0.24mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 40% ethyl acetate in dichloromethane. ¹HNMR (CDCl₃), δ (ppm): 7.87 (m, 2H), 7.71 (dd, 1H), 7.48 (m, 2H), 7.38(m, 2H), 4.52 (s, 2H), 3.67 (s, 3H), 2.41 (s, 3H).

Example 763-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-thiazol-4-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(30 mg, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (100 mg, 0.72 mmol),4-methyl-5-thiazol-4-yl-4H-[1,2,4]triazole-3-thiol (47.5 mg, 0.24 mmol)in acetonitrile (2 ml) at 60° C. overnight. Purification was performedon silica gel using 60% ethyl acetate in dichloromethane. ¹H NMR(CDCl₃), δ (ppm): 8.89 (d, 1H), 8.22 (d, 1H), 7.88 (m, 2H), 7.38 (m,2H), 4.55 (s, 2H), 3.94 (s, 3H), 2.41 (s, 3H).

Example 775-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(725 mg, 97%, white solid) was obtained from3-chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole (500 mg, 1.56 mmol),potassium carbonate (647 mg, 4.68 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (369 mg, 1.87 mmol)in acetonitrile (10 ml) at room temperature. Purification was performedby flash column chromatography on silica gel using 40% ethyl acetate inhexanes. ¹H NMR (CDCl₃), δ (ppm): 8.44 (d, 1H), 8.06 (d, 1H), 7.93 (d,1H), 7.51 (m, 2H), 7.26 (t, 1H), 7.19 (m, 1H), 4.54 (s, 2H), 3.73 (s,3H).

Example 785-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Ethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(28.1 mg, 27%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (59 mg, 0.30 mmol),3-chloromethyl-5-(3-ethyl-phenyl)-[1,2,4]oxadiazole (60 mg, 0.27 mmol)and potassium carbonate (111 mg, 0.80 mmol) in acetonitrile (1 ml) atroom temperature. Purification was performed by SPE (flash)chromatography using 50% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 7.90 (t, 2H), 7.51 (m, 2H), 7.42 (t, 2H) 7.18 (m, 1H), 4.52 (s,2H), 3.72 (s, 3H), 2.70 (m, 2H), 1.26 (t, 3H)

Example 792-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole

2-[5-(2-Methyl-pyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole(46.0 mg, 59%, white solid) was obtained from 2-mercaptobenzimidazole(41 mg, 0.27 mmol),4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-2-methyl-pyridine (50 mg, 0.24mmol), and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 ml) at roomtemperature. Purification was performed by SPE (flash) chromatographyusing 100% ethyl acetate and titurated with ether. ¹H NMR (DMSO-d₆), δ(ppm): 8.72 (d, 1H), 7.87 (s, 1H), 7.78 (d, 1H), 7.47 (t, 2H), 7.14 (m,2H), 4.81 (s, 2H), 2.59 (s, 3H)

Example 802-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole

2-[5-(3-Iodo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole(36 mg, 51%, white solid) was obtained from3-chloromethyl-5-(3-iodo-phenyl)-[1,2,4]oxadiazole (50 mg, 0.16 mmol),potassium carbonate (65 mg, 0.47 mmol), 1H-benzoimidazole-2-thiol (23mg, 0.16 mmol) in DMF (1 ml) at room temperature. Purification wasperformed by SPE (flash) chromatography using 50-100% ethyl acetate inhexanes followed by trituration with ethyl acetate. ¹H NMR (DMSO), δ(ppm): 12.73 (bs, 1H), 8.30 (s, 1H), 8.09 (d, 2H), 7.45 (m, 3H), 7.18(m, 2H), 4.78 (s, 2H).

Example 813-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(54.3 mg, 80%, clear oil) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40 mg, 0.19 mmol), potassiumcarbonate (79 mg, 0.58 mmol),4-methyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol (35.1 mg, 0.19mmol) in acetonitrile (2 ml) at 60° C. overnight. Purification wasperformed on silica gel using 50% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 7.87 (m, 2H), 7.41 (m, 2H), 4.59 (s, 2H), 3.69 (s,3H), 2.43 (s, 3H).

Example 822,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine

2,6-Dichloro-4-[4-methyl-5-(5-m-tolyl-[1,2,4]oxadiazol-3-ylmethylsulfanyl)-4H-[1,2,4]triazol-3-yl]-pyridine(51.4 mg, 62%, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40 mg, 0.19 mmol), potassiumcarbonate (79 mg, 0.58 mmol),5-(2,6-dichloro-pyridin-4-yl)-4-methyl-4H-[1,2,4]triazole-3-thiol (50.1mg, 0.19 mmol) in acetonitrile (2 ml) at 60° C. overnight. Purificationwas performed on silica gel using 80% ethyl acetate in hexanes. ¹H NMR(CDCl₃), δ (ppm): 7.87 (m, 2H), 7.61 (s, 2H), 7.40 (m, 2H), 4.60 (s,2H), 3.71 (s, 3H), 2.42 (s, 3H).

Example 833-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(4-Methyl-5-p-tolyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(57.8 mg, 81%, off-white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (40 mg, 0.19 mmol), potassiumcarbonate (79 mg, 0.58 mmol),4-methyl-5-p-tolyl-4H-[1,2,4]triazole-3-thiol (39.4 mg, 0.19 mmol) inacetonitrile (2 ml) at 60° C. overnight. Purification was performed onsilica gel using 80% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ (ppm):7.88 (m, 2H), 7.53 (d, 2H), 7.39 (m, 2H), 7.30 (d, 2H), 4.55 (s, 2H),3.59 (s, 3H), 2.42 (d, 6H).

Example 84Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine

Dimethyl-{3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]phenyl}-amine(28.0 mg, 85%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (18 mg, 0.093 mmol),3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-dimethyl-amine (20 mg,0.084 mmol), and potassium carbonate (35 mg, 0.25 mmol) in acetonitrile(1 ml) at room temperature. Purification was performed by SPE (flash)chromatography using 70% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 7.49 (m, 2H), 7.36 (m, 3H), 7.17 (t, 1H), 6.91 (d, 1H), 4.51 (s,2H), 3.72 (s, 3H), 3.00 (s, 6H)

Example 855-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(76.8 mg, 90%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (47 mg, 0.24 mmol),3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (50 mg, 0.22 mmol),and potassium carbonate (91 mg, 0.66 mmol) in acetonitrile (1 ml) atroom temperature. Purification was performed by SPE (flash)chromatography using 70% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 8.09 (s, 1H), 7.98 (d, 1H), 7.49 (m, 4H), 7.18 (m, 1H), 4.55 (s,2H), 3.73 (s, 3H)

Example 863-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethoxy-phenyl)[1,2,4]oxadiazole

3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(3-trifluoromethoxy-phenyl)[1,2,4]oxadiazole(144.0 mg, 91%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (78 mg, 0.39 mmol),3-chloromethyl-5-(3-trifluoromethoxy-phenyl)-[1,2,4]oxadiazole (100 mg,0.36 mmol) and potassium carbonate (149 mg, 1.08 mmol) in acetonitrile(2 ml) at room temperature. Purification was performed by SPE (flash)chromatography using 55% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 8.04 (d, 1H), 7.95 (s, 1H), 7.51 (m, 4H), 7.18 (m, 1H), 4.56 (s,2H), 3.74 (s, 3H)

Example 873-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(5-Cyclohexyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(10.5 mg, clear oil) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (165 mg, 1.20 mmol),5-cyclohexyl-4-methyl-4H-[1,2,4]triazole-3-thiol (94.6 mg, 0.48 mmol) inacetonitrile (3 ml) at 60° C. overnight. Purification was performed onsilica gel using 2% ammonia (2 N methanol) in dichloromethane. ¹H NMR(CDCl₃), δ (ppm): 7.88 (m, 2H), 7.39 (m, 2H), 4.42 (s, 2H), 3.46 (s,3H), 2.60 (m, 1H), 2.42 (d, 3H), 1.74 (m, 7H), 1.34 (m, 3H).

Example 883-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

3-(5-tert-Butyl-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(56.8 mg, white solid) was obtained from3-chloromethyl-5-m-tolyl-[1,2,4]oxadiazole (50 mg, 0.24 mmol), potassiumcarbonate (100 mg, 0.72 mmol),5-tert-butyl-4-methyl-4H-[1,2,4]triazole-3-thiol (41 mg, 0.24 mmol) inacetonitrile (2 ml) at 60° C. overnight. Purification was performed onsilica gel using 80% ethyl acetate in hexanes. ¹H NMR (CDCl₃), δ (ppm):7.89 (m, 2H), 7.40 (m, 2H), 4.46 (s, 2H), 3.63 (s, 3H), 2.43 (m, 3H),1.45 (s, 9H).

Example 895-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Bromo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(83.4 mg, 86%, white solid) was obtained from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (47 mg, 0.24 mmol),5-(3-bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole (60 mg, 0.22 mmol),and potassium carbonate (91 mg, 0.66 mmol) in acetonitrile (2 ml) atroom temperature. Purification was performed by SPE (flash)chromatography using 60% ethyl acetate in hexane. ¹H NMR (CDCl₃), δ(ppm): 8.25 (t, 1H), 8.02 (d, 1H), 7.73 (d, 1H), 7.50 (m, 2H), 7.40 (t,1H), 7.19 (m, 1H), 4.55 (s, 2H), 3.73 (s, 3H)

Example 902-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole

2-[5-(3-Bromo-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole(71.1 mg, 84%, white solid) was obtained from 2-mercaptobenzimidazole(35 mg, 0.23 mmol), 5-(3-Bromo-phenyl)-3-chloromethyl-[1,2,4]oxadiazole(60 mg, 0.22 mmol) and potassium carbonate (91 mg, 0.66 mmol) in DMF (2ml) at room temperature. Purification was performed by SPE (flash)chromatography using 35% ethyl acetate in hexane and titurated withether. ¹H NMR (DMSO-d₆), δ (ppm): 12.78 (broad s, 1H), 8.18 (s, 1H),8.07 (d, 1H), 7.93 (d, 1H), 7.59 (t, 1H), 7.46 (s, 2H), 7.14 (m, 2H),4.77 (s, 2H)

Example 915-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-(3-Methoxymethyl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(76 mg, 90%, white solid) was obtained from3-chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole (50 mg, 0.21mmol), potassium carbonate (87 mg, 0.63 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (50 mg, 0.25 mmol)in acetonitrile (2 ml) at room temperature. Purification was performedby SPE (flash) chromatography using 40-70% ethyl acetate in hexanes. ¹HNMR (CDCl₃), δ (ppm): 8.06 (s, 1H), 8.01 (d, 1H), 7.59 (d, 1H), 7.50 (m,3H), 7.18 (t, 1H), 4.54 (s, 2H), 4.50 (s, 2H), 3.72 (s, 3H), 3.43 (s,3H).

Example 922-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole

2-[5-(3-Methoxymethyl-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole(62 mg, 84%, white solid) was obtained from3-chloromethyl-5-(3-methoxymethyl-phenyl)-[1,2,4]oxadiazole (50 mg, 0.21mmol), potassium carbonate (87 mg, 0.63 mmol), 1H-benzoimidazole-2-thiol(32 mg, 0.21 mmol) in DMF (2 ml) at room temperature. Purification wasperformed by SPE (flash) chromatography using 40-100% ethyl acetate inhexanes. ¹H NMR (DMSO), δ (ppm): 8.09 (d, 2H), 7.59 (m, 2H), 7.46 (bs,2H), 7.14 (m, 2H), 4.77 (s, 2H), 4.51 (s, 2H), 3.35 (s, 3H).

Example 934-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine

A solution of isonicotinoyl chloride (2.0 g, 11.2 mmol) indichloromethane was treated with 2-chloro-N-hydroxy-acetamidine (1.58 g,14.6 mmol), followed by addition of triethylamine (4.67 ml, 33.6 mmol)in a dropwise manner. After stirring at room temperature 1 h, extractionwith ethyl acetate using water and brine washes afforded the oxy-acylintermediate (used without further purification, 150 mg, 0.7 mmol). Asolution of the crude product in acetonitrile (2 ml) and DMSO (2 ml)with K₂CO₃ (292 mg, 2.1 mmol) and4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (140 mg, 0.7 mmol)was stirred at room temperature for 24 h followed by 1.5 h at 120° C.(sealed tube). Standard aqueous work-up with ethyl acetate using waterand brine washes followed by silica gel chromatography afforded thetitle compound (110 mg, 44%). ¹H NMR (CDCl₃), δ (ppm): 8.41 dd, 2H),7.92 dd, 2H), 7.50 dd, 1H), 7.47 dd, 1H), 7.18 dd, 1H), 4.58 (s, 2H),3.74 (s, 3H); LC-MS (M+H)⁺: 357.

Example 94 was prepared in an analogous method to the procedure given inExample 93.

Example 944-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-pyridine

4-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-3-yl]-pyridine(12 mg, 5%) was obtained from N-hydroxy-isonicotinamidine (200 mg, 1.4mmol) with chloroacetyl chloride (0.11 ml, 1.4 mmol) and triethylamine(0.5 ml, 3.5 mmol); aqueous work-up gave intermediate (150 mg, 0.7mmol); treated with K₂CO₃ (292 mg, 2.1 mmol), and4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (140 mg, 0.7 mmol).Purification was performed by silica gel chromatography andrecrystallization. ¹H NMR (CDCl₃), δ (ppm): 8.76 (dd, 2H), 7.89 (dd,2H), 7.53 (dd, 1H), 7.48 (dd, 1H), 7.18 (dd, 1H), 4.71 (s, 2H), 3.73 (s,3H); LC-MS (M+H)+: 357.

Example 952-{1-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-1H-imidazo[4,5-b]pyridineand2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H-imidazo[4,5-b]pyridine

THF (3 ml) was added to a mixture of sodium hydride (60%, 8 mg, 0.2mmol) and2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]1-H-imidazo[4,5-b]pyridine(24.6 mg, 0.072 mmol) and the resulting mixture was stirred at 0° C. forabout 15 min. Methyl iodide (20 μL, 0.32 mmol) was added the resultingmixture was stirred at 0° C. for 2 h. The reaction was quenched by theaddition of dichloromethane (10 ml) and water (2 ml). After vigorousstirring, the organic extracts (10 ml, plus 3×5 ml) were eluted througha Chem Elut Extraction Column (Varian, cat #1219-8002). Purificationusing SPE chromatography (5 g silica) using 25/25/50 to 50/25/25 ethylacetate/dichloromethane/hexane yielded two products. The first productto elute was2-{1-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-1-methyl-1H-imidazo[4,5-b]pyridine(6 mg, 23%). ¹H NMR (CDCl₃), δ (ppm): 8.46 (d, 1H), 7.72 (d, 1H), 7.62(d, 1H), 7.55 (d, 1H), 7.42 (t, 1H), 7.14 (m, 2H), 5.67 (q, 1H), 3.88(s, 3H), 3.71 (s, 3H), 2.01 (d, 3H).

The second product to elute was2-[5-(3-methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1-methyl-1H-imidazo[4,5-b]pyridine(12 mg, 47%). ¹H NMR (CDCl₃), δ (ppm): 8.44 (d, 1H), 7.69 (d, 1H), 7.60(d, 1H), 7.55 (d, 1H), 7.41 (t, 1H), 7.13 (m, 1H), 4.90 (s, 2H), 3.87(s, 3H), 3.70 (s, 3H).

Example 96-97 was prepared in an analogous method to the procedure givenin Example 95.

Example 963-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[1-Methyl-1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole(13 mg, 47%) was obtained from3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(25.5 mg, 0.069 mmol) with 60% sodium hydride (37 mg, 0.92 mmol) andmethyl iodide (0.10 ml, 1.6 mmol) in THF (3 ml) at room temperature for2 h. The product was extracted with ethyl acetate and purified by SPE20-40% ethyl acetate in 1:1 dichloromethane:hexane. ¹H NMR (CDCl₃), δ(ppm): 7.83 (br s, 2H), 7.48 (d, 1H), 7.42 (d, 1H), 7.36 (m, 2H), 7.13(m, 1H), 3.50 (s, 3H), 2.35 (s, 3H), 1.95 (s, 6H).

Example 973-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole

3-[1-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-5-m-tolyl-[1,2,4]oxadiazole(6.1 mg, 17%) was obtained from3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(33.8 mg, 0.091 mmol) with 60% sodium hydride (17 mg, 0.42 mmol) andmethyl iodide (20 μL, 0.32 mmol) in THF (2.5 ml) at room temperature for1 h. The product was extracted with dichloromethane and purified by SPE25-40% ethyl acetate in 1:1 chloroform:hexane. ¹H NMR (CDCl₃), δ (ppm):7.89 (br s, 2H), 7.50 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.16 (m, 1H),4.89 (q, 1H), 3.64 (s, 3H), 2.37 (s, 3H), 1.90 (d, 3H).

Example 983-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-[1,2,4]oxadiazoleand3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-tolyl-[1,2,4]oxadiazole

Dichloromethane (2.5 ml) was added to a mixture of3-chloro-benzenecarboperoxoic acid (57-85%, 49.5 mg, 0.16-0.25 mmol) and3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(45 mg, 0.12 mmol) and the resulting mixture was stirred at roomtemperature overnight. The reaction was quenched by the addition ofdichloromethane (10 ml) and 1 M sodium hydroxide (3 ml). After vigorousstirring, the organic extracts (10 ml, plus 3×5 ml) were eluted througha Chem Elut Extraction Column (Varian, cat #1219-8002). Purification wasperformed by SPE chromatography (5 g silica) using 10-30% ethyl acetatein 1:1 dichloromethane:hexane yielded two products. The first product toelute was3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfonylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(12.3 mg, 25%). ¹H NMR (CDCl₃), δ (ppm): 7.83 (br s, 2H), 7.63 (d, 1H),7.56 (d, 1H), 7.36 (m, 2H), 7.24 (m, 1H), 5.12 (s, 2H), 3.94 (s, 3H),2.36 (d, 3H).

The second product to elute was3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-sulfinylmethyl)-5-m-tolyl-[1,2,4]oxadiazole(33.2 mg, 71%). ¹H NMR (CDCl₃), δ (ppm): 7.87 (br s, 2H), 7.59 (d, 1H),7.54 (d, 1H), 7.38 (m, 2H), 7.22 (m, 1H), 5.05 (d_(AB), 1H), 4.90(d_(AB), 1H), 4.03 (s, 3H), 2.39 (d, 3H).

Example 995-(3-Furan-3-yl-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

To5-(3-Iodo-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole(50 mg, 0.10 mmol) in a vial was added 3-furan boronic acid (17 mg, 0.16mmol), tetrakis(triphenylphosphine)palladium(0) (6 mg, 0.0052 mmol),ethylene glycol dimethyl ether (1 ml) and 2 M sodium carbonate (1 ml).The vial was then sealed and heated at 90° C. for 1 h with vigorousstirring. The reaction was cooled, diluted with ethyl acetate, washedwith water and saturated brine, filtered and concentrated. The residuewas purified by flash column chromatography using 70% ethyl acetate inhexanes. Additional purification by trituration with a mixture ofdiethyl ether and hexanes and then filtration afforded the titlecompound as a beige solid 25 mg (57%). ¹H NMR (CDCl₃), δ (ppm): 8.18 (s,1H), 7.98 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.51 (m, 4H), 7.17 (m,1H), 6.74 (s, 1H), 4.55 (s, 2H), 3.73 (s, 3H).

Intermediates

Example 100 Pyrimidine-4-carboxylic acid

3-Methyl-pyrimidine (9.41 g, 100 mmol), potassium permanganate (26.9 g)and sodium carbonate (10.6 g) was refluxed in water (100 ml) for 72 hfollowed by filtration through celite. The filtrate was washed withseveral portions of DCM and EtOAc before acidification with conc. HCl.The formed precipitate was collected and washed with water to yield 1.37g of the title compound as a white solid. 1H NMR (DMSO-d6) d (ppm):13.94 (br. s, 1H), 9.37 (d, 1H), 9.07 (d, 1H), 8.01 (dd, 1H).

Example 101 5-Chloro-thiophene-3-carboxylic acid

Thiophene-3-carboxylic acid (17.51 g, 136.6 mmol) and1-chloro-pyrrolidine-2,5-dione (23.7 g) was refluxed in acetic acid (200ml) for 4 h under argon before pouring onto water (700 ml). Repeatedextraction with several small portions of DCM, followed by backextraction from the combined organics with several small portions of 2 Maqueous sodium hydroxide, gave a combined alkaline aqueous solution thatwas washed with DCM before acidified with conc. HCl to precipitate thecrude material. This precipitate was recrystallized from water to yield14.98 g of the title compound as a grey solid contaminated withapproximately 20 mol % of a dichlorinated byproduct as judged from MSand 1H-NMR. 1H NMR (DMSO-d6) d (ppm): 8.15 (d, 1H), 7.37 (d, 1H).

Example 102 3-Methylsulfanyl-benzoic acid

Methyl iodide (0.972 mL) was added to a mixture of 3-mercapto-benzoicacid (601 mg, 3.9 mmol) and potassium carbonate (2.7 g, 19.5 mmol) inDMF (8 mL) in an ice-bath. After the reaction was warmed to roomtemperature and stirred for 1 hour, the reaction mixture was dilutedwith ethyl acetate, washed with water (3×), dried over anhydrous sodiumsulfate, filtered, and concentrated to afford 3-methylsulfanyl-benzoicacid methyl ester (684 mg, 96%, yellow oil). ¹H NMR (CDCl₃), δ (ppm):7.90 (s, 1H), 7.80 (d, 1H), 7.44 (d, 1H), 7.35 (t, 1H), 3.92 (s, 3H),2.53 (s, 3H).

3-Methylsulfanyl-benzoic acid methyl ester (684 mg, 3.8 mmol) and 1NNaOH (5.6 mL, 5.6 mmol) in methanol (8 mL) and THF (8 mL) were heated at70° C. for 1 hour. The reaction mixture was concentrated and then theresidue was diluted with water. After acidification with 1N HCl to pH˜2,the aqueous layer was extracted with ethyl acetate and then washed withwater and saturated brine, dried over anhydrous sodium sulfate,filtered, and concentrated to afford 3-methylsulfanyl-benzoic acid (616mg, 97%, white solid). ¹H NMR (DMSO), δ (ppm): 13.1 (bs, 1H), 7.76 (s,1H), 7.70 (d, 1H), 7.51 (d, 1H), 7.44 (t, 1H), 2.52 (s, 3H).

Example 103 3-Cyclopropyl-benzoic acid

1.0 M Diethyl zinc in hexanes (27.3 ml, 27.3 mmol) was added to asolution of 2,4,6-trichlorophenol (5.4 g, 27.3 mmol) in dichloromethane(100 ml) at −40° C. After stirring for 15 minutes, diiodo-methane (2.2mL, 27.3 mmol) was added at −40° C. and stirred for an additional 15minutes. 1-Bromo-3-vinyl-benzene (2.5 g, 13.7 mmol) was then added tothe reaction mixture, allowed to warm to room temperature, and leftstirring overnight. The reaction mixture was diluted withdichloromethane, washed with 1N HCl (2×), saturated sodium bicarbonate(2×), saturated sodium sulfite, 1N sodium hydroxide, and saturatedbrine, dried over magnesium sulfate, filtered and concentrated. GC-MSrevealed that the reaction mixture contained1-Bromo-3-cyclopropyl-benzene and 1-bromo-3-vinyl-benzene.

To remove the bromo-3-vinyl-benzene, the crude mixture was reacted withpotassium permanganate. A solution of potassium permanganate/water (1.5g/20 mL) was added drop-wise to a solution of the crude mixture (−3.5 g)in THF (40 mL) at 0° C. and then allowed to warm to room temperature.After 1 hour, the reaction was diluted with diethyl ether, washed withwater and saturated brine, dried over anhydrous sodium sulfate filteredand concentrated. Purification by flash column chromatography elutedwith 100 hexanes afforded 1-bromo-3-cyclopropyl-benzene (2.20 g, 81%).

1.6 M n-Butyllithium in hexanes (3.2 mL, 5.1 mmol) was added drop-wiseto a solution of 1-bromo-3-cyclopropyl-benzene at −78° C. and stirredfor 1 hour. This reaction mixture was then transferred via canula to a250 mL round bottom flask equipped with a stirrer bar approximately ¼full of solid carbon dioxide and stirred and for 1 hour. The reactionmixture was concentrated and then the residue was diluted with water.The aqueous layer was washed with dichloromethane (3×), acidified with 1N HCl to pH˜2, and extracted with ethyl acetate. The organic phase waswashed with water and saturated brine, dried over anhydrous sodiumsulfate, filtered and concentrated to afford 3-cyclopropyl-benzoic (356mg, 43%, white solid). ¹H NMR (DMSO), δ (ppm): 12.90 (bs, 1H), 7.71 (d,1H), 7.64 (s, 1H), 7.34 (m, 2H), 2.01 (m, 1H), 0.99 (m, 2H), 0.70 (m,2H).

Example 104 3-tert-Butoxycarbonylamino-benzoic acid

To a flask containing ethyl-3-aminobenzoate (1 g, 6.05 mmol) addeddi-tert-butyl dicarbonate (3.16 g, 14.5 mmol), triethyl amine (500 mg,4.94 mmol), and THF (10 mL) and allowed to stir at 60° C. for two hoursand then overnight at room temperature. The THF was removed in vacuo,and the crude ester was partitioned between ethyl acetate and water,washed with saturated brine, dried over anhydrous sodium sulfate and thesolvent was removed in vacuo. The product was then purified by flashcolumn chromatography using 15% ethyl acetate in hexane affording 2 g of3-tert-butoxycarbonylamino-benzoic aid ethyl ester (white slurry).

To the crude 3-tert-butoxycarbonylamino-benzoic acid ethyl ester (˜2.0g, 0.00754 mmol) added THF (15 mL), and 0.5M LiOH (15 mL). The mixturewas heated for two hours at 75° C. and the THF was removed in vacuoafter cooling. The precipitate was filtered from the remaining mixtureand the filtrate was transferred to a separatory funnel. The aqueouslayer was washed with dichloromethane (3×) and was acidified to pH˜5using 1M HCl. The product was then extracted with ethyl acetate, washedwith water, saturated brine, dried over anhydrous sodium sulfate,filtered and concentrated. 730 mg of 3-tert-Butoxycarbonylamino-benzoicacid (white solid) was isolated. 1H NMR (DMSO-d₆) δ (ppm): 9.58 (s, 1H),8.16 (s, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.37 (t, 1H), 1.49 (s, 9H)

Example 105 3-Acetyl-benzoic acid

6M Sodium hydroxide (25 mL) was added to 3-acetylbenzonitrile (850 mg,5.82 mmol) in methanol (25 mL) and then heated at 90° C. overnight.After concentrating the reaction mixture, the aqueous layer was washedwith dichloromethane (2×), then acidified pH˜3 with 12M HCl. Theprecipitate was extracted with ethyl acetate then washed with water andsaturated brine, dried over anhydrous sodium sulfate filtered andconcentrated to afford 3-ethylbenzoic acid as a colorless oil; 0.800 g(92%). 1H NMR (CDCl₃) δ (ppm): 8.70 (s, 2H), 8.33 (d, 2H), 8.24 (d, 2H),7.64 (t, 1H), 2.70 (s, 3H).

Example 106 2-Methyl-isonicotinic acid hydrazide

Dichloromethane (10 mL) was added to 2-methyl nicotinic acidhydrochloride salt (1.1 g, 6.34 mmol) and oxalyl chloride (6.95 mL, 13.9mmol) was added slowly under Argon while the flask was cooled in ice.Dimethylformamide (2 drops) was added and the reaction was allowed tostir overnight during which time it warmed to room temperature. Thereaction was concentrated and THF (10 mL) was added to the flask and itwas placed in an ice bath. Methanol (5 mL) was added and the reactionwas allowed to stir for one hour. The reaction was concentrated and theresidue was partitioned between NaHCO₃ (sat) and EtOAc. The product wasextracted with EtOAc three times. The combined organic layers werewashed with brine, dried over Na₂SO₄, filtered and concentrated.Purification was performed by solid phase extraction tube (20%EtOAc/hexanes) gave the title compound as a clear oil. ¹H NMR CDCl₃

(ppm): 8.51 (d, 1H), 7.57 (d, 1H), 7.51 (d, 1H), 3.82 (s, 3H), 2.50 (s,3H).

2-Methyl-isonicotinic acid methyl ester (316.5 mg, 2.093 mmol) wasdissolved in MeOH (7 mL) under Argon and hydrazine monohydrate 98% (1mL, 20.93 mmol) was added. The reaction was allowed to stir under Argonat room temperature for eighteen hours. The reaction was concentrated togive the title compound (271.9 mg, 86%) as a white solid. ¹H NMR CDCl₃

(ppm): 8.59 (d, 1H), 7.50 (s, 1H), 7.38 (d, 1H), 3.09 (br. s, 3H), 2.60(s, 3H).

Example 107 5-Chloro-2-fluoro-benzoic acid hydrazide

Step 1: 5-Chloro-2-fluoro-benzoic acid methyl ester: Methanol (20 ml)was added to a solution 5-chloro-2-fluoro-benzoyl chloride (1.2 g, 6.2mmol) in dichloromethane (10 ml) in an ice-bath. The reaction mixturewas warmed to room temperature, stirred for 3 h and then concentrated toafford 5-chloro-2-fluoro-benzoic acid methyl ester (0.17 g, 100%). 1HNMR (CDCl₃), δ (ppm): 7.93 (m, 1H), 7.48 (m, 1H), 7.12 (m, 1H), 3.96 (s,3H). Step 2: 5-Chloro-2-fluoro-benzoic acid hydrazide: A mixture of5-chloro-2-fluoro-benzoic acid methyl ester (0.17 g, 6.2 mmol) andhydrazine monohydrate (0.451 ml, 9.3 mmol) in ethanol (20 ml) wasstirred at room temperature overnight. The reaction mixture wasconcentrated and then the residue was triturated with diethyl ether toafford 5-chloro-2-fluoro-benzoic acid hydrazide (497 mg, 42%, whitesolid). 1H NMR (DMSO), δ (ppm): 9.66 (bs, 1H), 7.58 (m, 2H), 7.36 (m,1H), 4.58 (bs, 2H).

Example 108 was prepared analogously to example 107.

Example 108 3-Cyano-benzoic acid hydrazide

3-cyano-benzoyl chloride (3 g, 18.12 mmol) in dichlormethane (5 mL) andmethanol (20 mL) was stirred at room temperature and overnight. Thesolvent was removed using a rotevaporator to afford a white solid (3.76g). ¹H NMR (DMSO) □ (ppm): 8.33 (m, 1H), 8.24 (m, 1H), 8.14 (m, 1H),7.76 (m, 1H), 3.89 (d, 3H).

A mixture of 3-cyano-benzoic acid methyl ester (2 g, 12 mmol) andhydrazine monohydrate (0.60 mL, 12 mmol) in ethanol (10 mL) was stirredat room temperature overnight. The reaction mixture was concentrated andthen the residue was triturated with diethyl ether to afford3-cyano-benzoic acid hydrazide (1.02 g, 51%, pink solid). ¹H NMR (DMSO)

(ppm): 10.31 (s, 1H), 8.21 (m, 1H), 8.11 (m, 1H), 7.99 (m, 1H), 7.70 (m,1H), 4.50 (s, 1H).

Example 109 2-Chloro-isonicotinic acid hydrazide

HOBt (823 mg, 6.09 mmol), and EDCI (1.2 g, 6.09 mmol) were added to asuspension of 2-chloro-isonicotinic acid (800 mg, 5.08 mmol) inacetonitrile (10.3 ml) at room temperature. After two h a solution ofhydrazine monohydrate (0.493 ml, 10.2 mmol) in acetonitrile (5.0 ml) wasadded drop-wise at 0° C. After 30 min, the solvent was removed using aroto-evaporator and the residue was diluted with ethyl acetate, quenchedwith water, dried over sodium sulfate, filtered and concentrated toafford 2-chloro-isonicotinic acid hydrazide (493 mg, 57%, yellow solid).1H NMR (DMSO) d (ppm): 10.21 (bs, 1H), 8.55 (d, 1H), 7.82 (s, 1H), 7.75(d, 1H), 4.69 (bs, 2H).

The following compounds were prepared analogously to example 109:Example No. 1) Name 110 2-Fluoro-5-methyl-benzoic acid hydrazide 111Pyrimidine-4-carboxylic acid hydrazide

The following compounds were prepared analogously to Example 6: ExampleNo. Name 112 3-Fluoro-N-hydroxy-benzamidine 113N-Hydroxy-thiophene-3-carboxamidine 1142-Chloro-N-hydroxy-propionamidine 115 3,N-Dihydroxy-benzamidine 116N-Hydroxy-2-methyl-benzamidine 117N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine 118 3-Chloro-N-hydroxy-benzamidine 119N-Hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine 120 2,5-Difluoro-N-hydroxy-benzamidine

The following compounds were prepared analogously to Example 31: ExampleNo. Name 121 4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 1224-Butyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1234-(3-Methoxy-propyl)-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1244-Benzyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1254-Furan-2-ylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1265-Thiophen-2-yl-4-thiophen-2-ylmethyl-4H-[1,2,4]triazole-3-thiol 1274-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1284-Furan-2-ylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 1294-Ethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 1304-Ethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 1314-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol 1324-Furan-2-ylmethyl-5-pyridin-3-yl-4H-[1,2,4]triazole-3-thiol 1334-Ethyl-5-furan-2-yl-4H-[1,2,4]triazole-3-thiol 1344-Ethyl-5-(3-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol 1354-Ethyl-5-(4-fluoro-phenyl)-4H-[1,2,4]triazole-3-thiol 1365-(2-Fluoro-5-methyl-phenyl)-4-furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol137 4-Ethyl-5-(3-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 1384-Ethyl-5-(5-methyl-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 1395-(2-Chloro-6-methyl-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol140 5-(5-Bromo-furan-2-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1414-Ethyl-5-(3-methoxy-thiophen-2-yl)-4H-[1,2,4]triazole-3-thiol 1424-Ethyl-5-(tetrahydro-furan-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione143 4-Ethyl-5-thioxo-4,5-dihydro-1H-[1,2,4]triazole-3-carboxylic acidmethyl ester

The following compounds were prepared analogously to Example 36: Exam-ple No. Name 1445-(2-Chloro-pyridin-4-yl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1455-(2-Chloro-6-methoxy-pyridin-4-yl)-4-ethyl-4H- [1,2,4]triazole-3-thiol146 4-Ethyl-5-(3-methyl-3H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol 1474-Propyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 1484-Ethyl-5-(1-methyl-1H-imidazol-2-yl)-4H-[1,2,4]triazole-3-thiol 1494-Ethyl-5-(1-methyl-1H-imidazol-4-yl)-4H-[1,2,4]triazole-3-thiol 1503-(5-Mercapto-4-methyl-4H-[1,2,4]triazol-3-yl)-benzonitrile 1515-(3-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1525-(4-Chloro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1535-(2-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1545-(3-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1555-(4-fluoro-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1565-Benzo[b]thiophen-2-yl-4-methyl-4H-[1,2,4]triazole-3-thiol 1575-(3-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1585-(4-methoxy-phenyl)-4-methyl-4H-[1,2,4]triazole-3-thiol 1594-Ethyl-5-(4-methoxy-phenyl)-4H-[1,2,4]triazole-3-thiol 1605-(3,5-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1615-(2,6-Difluoro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1625-(4-Butoxy-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1635-Benzo[1,3]dioxol-5-yl-4-ethyl-4H-[1,2,4]triazole-3-thiol 1644-Ethyl-5-pyrimidin-5-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1654-Ethyl-5-furan-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1664-(Tetrahydrofuran-2-ylmethyl)-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1675-Cyclopentyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1684-Ethyl-5-[2-(4-methoxy-phenyl)-ethyl]-2,4-dihydro-[1,2,4]triazole-3-thione

Example 169 5-(3,5-Dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol

3,5-Dichloro-benzoic acid (382 mg, 2 mmol) was mixed with triethylamine(606 mg, 3 mmol) in THF (6 ml) at 10° C. Then isobutyl chloroformate(300 mg, 2.2 mmol) was added dropwise and stirred for 45 min. To thereaction mixture, 4-methyl-3-thiosemicarbazide (238.4 mg, 2 mmol) wasadded. After being stirred at room temperature for 10 min, the reactionmixture was heated to 70° C. overnight. Standard work-up. The productwas purified by column chromatography with 25˜30% ethyl acetate inhexanes to give 46.4 mg (8.5%) of5-(3,5-dichloro-phenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol.

The following compounds were prepared analogously to Example 169:Example No. Name 1705-(3-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1715-(4-Methylphenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1724-Ethyl-5-(3-nitrophenyl)-4H-[1,2,4]triazole-3-thiol 1735-(2,5-Difluorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1745-(3-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol 1755-(4-Chlorophenyl)-4-ethyl-4H-[1,2,4]triazole-3-thiol

Example 176 4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione

Step 1: N-Ethyl-2-(methoxyacetyl)hydrazinecarbothioamide: Methoxyaceticacid (360 mg, 3.99 mmol), 4-ethyl-3-thiosemicarbazide (581 mg, 4.87mmol), diisopropylcarbodiimide (615 mg, 4.87 mmol) andhydroxybenzotriazole (69.6 mg, 0.51 mmol) were mixed indimethylformamide (10 ml) and stirred under argon at ambienttemperatures for 19 h. After evaporation to dryness the crude was useddirectly in the next step. MS (ESI) m/z 192 (M+1). Step 2:4-Ethyl-5-methoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione:N-Ethyl-2-(methoxyacetyl)hydrazinecarbothioamide (760 mg crude, 4 mmol)and sodium bicarbonate (560 mg, 6.6 mmol) were suspended in water (15ml) and refluxed for 5 h. After cooling and filtration the filtrate wasacidified with concentrated hydrochloric acid, followed by extractionwith ethyl acetate. After evaporation to dryness the crude wasrecrystallized in ethyl acetate/heptane. Filtration andrecrystallization of the mother liquor gave a combined yield of 325 mg(47%) of the title compound. 1H NMR (CDCl₃), δ (ppm): 4.47 (s, 2H), 4.13(q, 2H), 3.37 (s, 3H), 1.38 (t, 3H).

The following compounds were prepared analogously to Example 176:Example No. Name 1774-Methyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1784-Allyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1794-Ethyl-5-(4-methoxy-phenoxymethyl)-2,4-dihydro-[1,2,4]triazole-3-thione180 4-Ethyl-5-phenoxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1814-Ethyl-5-hydroxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1824-Ethyl-5-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione 1834-Ethyl-5-methylsulfanylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1845-Ethoxymethyl-4-ethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1855-Furan-3-yl-4-methyl-2,4-dihydro-[1,2,4]triazole-3-thione 1864-Methyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1874-Ethyl-5-pyridazin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1884-Ethyl-5-pyridin-4-ylmethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1894-Ethyl-5-(6-hydroxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione190 4-Ethyl-5-(4-hydroxy-phenyl)-2,4-dihydro-[1,2,4]triazole-3-thione191 4-Ethyl-5-p-tolyloxymethyl-2,4-dihydro-[1,2,4]triazole-3-thione 1924-Ethyl-5-(6-methoxy-pyridin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione1934-Ethyl-5-(2-methoxy-pyridin-4-yl)-2,4-dihydro-[1,2,4]triazole-3-thione194 4-Ethyl-5-pyrimidin-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione 1954-Ethyl-5-(5-methoxy-pyrimidin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione

Example 196 4-Furan-2-ylmethyl-4H-[1,2,4]triazole-3-thiol

A solution of formic acid hydrazide (439 mg, 7.809 mmol) in pyridine (20ml) was added to a solution of 2-isothiocyanatomethyl-furan (1 g, 7.185mmol) in pyridine (20 ml). Reaction took place at room temperatureovernight, and ethanol (20 ml) was added directly to the reaction andplaced in 80 C bath overnight. Solvent was evaporated and the titlecompound (1.09 g, 83%) was obtained from purification by SPEchromatography on silica gel with 500 ml 20%, 250 ml 25%, 250 ml 30%,250 ml 35%, 250 ml 40%, and 250 ml 50% ethyl acetate in hexanes. 1H NMR(CD3OD), δ(ppm): 14.0 (bs, 1H), 8.19 (s, 1H), 7.52 (q, 1H), 6.52 (m,1H), 6.42 (m, 1H), 4.90 (s, 2H).

The following compounds were prepared analogously to Example 196:Example No. Name 1974-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol 1984-Cyclopropylmethyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol

Example 1994-Cyclopropyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione

To a slurry of thiophene-2-carboxylic acid hydrazide (866 mg, 6.09 mmol)in iPrOH (25 ml) was added isothiocyanato-cyclopropane (602 mg, 6.08mmol). The mixture was stirred at 70° C. for 72 h and then cooled toroom temperature. The white precipitate was filtered off and suspendedin a MeOH:H₂O (9:1, 40 ml) together with aq. NaOH (2%, 5 ml). Thereaction mixture was stirred at 70° C. overnight and then cooled to roomtemperature. The pH was adjusted to around 4 with aq. HCl (1N). Theformed white precipitate was filtered off, washed with water and driedunder vacuum (829 mg, 61%). 1H NMR (CD3OD), δ (ppm): 7.67 (dd, 1H), 7.63(dd, 1H), 7.17 (dd, 1H), 3.15 (m, 1H), 1.14 (m, 2H), 0.86 (m, 2H).

The following compounds were prepared analogously to Example 199:Example No. Name 2005-Furan-2-yl-4-(2-methoxy-ethyl)-2,4-dihydro-[1,2,4]triazole-3-thione201 4-Cyclopropyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione 202(3-Thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic acidmethyl ester 2034-Cyclopropylmethyl-5-thiophene-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione2044-(2-Methoxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione205Thiophen-2-yl-4-(2,2,2-trifluoroethyl)-2,4-dihydro-[1,2,4]triazole-3-thione206 4-Cyclopropyl-5-pyrimidin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione207 4-Cyclopropyl-5-pyridin-3-yl-2,4-dihydro-[1,2,4]triazole-3-thione

Example 208 4-Ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol

To a solution of 4-ethyl-3-thiosemicarbazide (2.38 g, 20 mmol) andtriethylamine (6.06 g, 60 mmol) in THF (30 ml), trifluoroaceticanhydride (5.04 g, 24 mmol) was added. The reaction mixture was stirredat room temperature for an h and heated at 60° C. overnight. Standardwork-up, the product was triturated with hexanes to give 564 g of as4-ethyl-5-trifluoromethyl-4H-[1,2,4]triazole-3-thiol pale-brown solid.1H-NMR (CDCl₃) d (ppm): 12.64 (w, 1H), 4.22 (q, 2H) and 1.44 (t, 3H).

Example 209 4-Ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole

The title compound was synthesized according to the method described inÅkerblom et al. J. Med. Chem. 16, 312 (1973).4-Ethyl-3-methylsulfanyl-5-thiophen-2-yl-4H-[1,2,4]triazole (1.14 g,5.06 mmol) was dissolved in glacial acetic acid (20 ml) followed by theaddition of 30% hydrogen peroxide (5 ml). After stirring at ambienttemperatures for 16 h additional 30% hydrogen peroxide (5 ml) was added.The mixture was stirred for 3 h at ambient temperature, then heated to100° C. for 2.5 h. After cooling in an ice/water bath the reaction wasneutralized with sodium hydroxide and extracted twice withdichloromethane. The organic layers were combined, evaporated to drynessand dried in vacuo yielding the title compound (0.78 g, 60%). 1H NMR(CDCl₃), δ (ppm): 7.60 (d, 1H), 7.56 (d, 1H), 7.22 (m, 1H), 4.51 (q,2H), 3.58 (s, 3H), 1.55 (t, 3H).

The following compound was prepared analogously to Example 209: Exam-ple No. Name 2104-(5-Methanesulfonyl-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

Example 2114-(2-Hydroxy-ethyl)-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione

To a slurry of LAH (38.1 mg, 1.00 mmol) in anhydrous THF (8 ml) was dropwise added(3-thiophen-2-yl-5-thioxo-1,5-dihydro-[1,2,4]triazol-4-yl)-acetic acid(101 mg, 0.42 mmol) in anhydrous THF (4 ml). The mixture was reacted for2 h and then quenched with saturated aq. Na₂SO₄ (10 ml). THF was removedunder reduced pressure and the residue was made acidic with aq. HCl (3N)and partitioned between EtOAc and water. The aqueous layer was extractedwith EtOAc (3×20 ml). The combined organic layers were washed with brine(15 ml), dried (MgSO₄) and concentrated under reduced pressure. Thecrude product was used without purification in the next step. 1H NMR(DMSO-d6), δ (ppm): 13.94 (s, 1H), 7.86 (d, 1H); 7.81 (d, 1H), 7.24 (dd,1H), 5.09 (t, 1H), 4.16 (t, 2H), 3.76 (app. q, 2H).

Example 212 4-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine

860 μl (10 mmol) oxalyl chloride was slowly added to a solution of 731mg (10 mmol) N-methyl-acetamide and 2.33 ml (20 mmol) 2,6-lutidine in 20ml CH₂Cl₂ at 0° C. After 15 min 1.37 g (10 mmol) isonicotinic acidhydrazide was added in one portion. The resulting mixture was stirred atroom temperature for 1 h and the neutralized with NaHCO₃(sat). Thephases were separated and the water phase was extracted with CH₂Cl₂. Thecombined organic phases were dried and concentrated. The residue wasdissolve in 20 ml acetic acid and heated at 120° C. for 2 h. Aftercooling the solvent was removed. Flashchromatography (CH2Cl2/MeOH 10:1)afforded 765 mg (44%) of a grey/white solid. 1H NMR (CDCl₃), d (ppm):2.52 (s, 3H) 3.66 (s, 3H) 7.58 (d, 2H) 8.76 (d, 2H).

Example 213Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine

A mixture of 1000 mg (4.35 mmol) N-amino-N′,N″-dimethyl-guanidinehydriodide (Henry; Smith; J. Amer. Chem. Soc.; 73; 1951; 1858) and 774mg (4.35 mmol) isonicotinoyl chloride hydrochloride in 3 ml of pyridinewas heated with microwaves for 5 min at 160° C. K₂CO₃(sat) was added andthe mixture was extracted 4 times with CHCl₃. The organic phase wasdried and concentrated. Recrystallization from ethanol, water and EtOAcgave 216 mg (26%) of a yellow white solid. 1H NMR (DMSO), d (ppm): 2.85(d, 3H) 3.45 (s, 3H) 6.25 (d, 1H) 7.65 (m, 2H) 8.67 (m, 2H).

Example 2143-Pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine

A solution of 750 mg (3.1 mmol)(1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (ref. Krezel,Izabella; Pharmazie; EN; 49; 1; 1994; 27-31) and 552 mg (3.1 mmol)isonicotinoyl chloride hydrochloride in 3 ml pyridine was heated at 120°C. over night. The reaction mixture was cooled and diluted withK₂CO₃(sat) and extracted with 3×10 ml chloroform. The combined organicextracts were dried and concentrated. Flashchromatography (CH₂Cl₂/MeOH10:1) afforded 83 mg (18%) of a white solid. 1H NMR (CDCl₃), d (ppm):1.91 (m, 2H) 3.24 (m, 2H) 4.13 (m, 2H) 7.67 (m, 2H) 8.65 (m, 2H).

The following compound was prepared analogously to Example 214: ExampleNo. Name 215 3-Furan-2-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine

Example 2164-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione

Step 1: 6-Chloro-pyridazine-3-carboxylic acid: Potassium dichromate (3.3g, 11.2 mmol) was added in portions to a solution of3-Chloro-6-methyl-pyridazine (1.2 g, 9.3 mmol) in H₂SO₄ (10 ml). Afteraddition the mixture is stirred at 50° C. on. The reaction was pored onice and the mixture was extracted three times with diethyl ether. Thecombined organic phases were dried and concentrated to give the titlecompound (840 mg, 57%). LC-MS (M++1): 159 and 161 (3:1). Step 2:6-Chloro-pyridazine-3-carboxylic acid methyl ester: A solution of6-chloro-pyridazine-3-carboxylic acid (700 mg, 4.53 mmol) in thionylchloride (15 ml) was refluxed for 3 h. The reaction was cooled toambient temperature and evaporated to dryness. Sodium methoxide (244 mg,4.53 mmol) in MeOH (20 ml) was added to the residue and the solution wasstirred on at room temperature (rt). H₂O was added and the mixture wasextracted three times with DCM. The combined organic phases were driedand concentrated. Flashchromatography (SiO₂, Heptane/EtOAc 1:1) afforded560 mg (72%) of the title compound. 1H NMR (CDCl₃), δ (ppm): 4.09 (s,3H), 7.69 (d, 1H), 8.18 (d, 1H). LC-MS (M⁺+1): 173 and 175 (3:1). Step3: 6-Methoxy-pyridazine-3-carboxylic acid methyl ester: A solution of6-chloro-pyridazine-3-carboxylic acid methyl ester in NaOMe in MeOH (1M,10 ml) was refluxed on. H₂O was added and the mixture was extractedthree times with DCM to give organic phase I. The combined organicphases I were dried and concentrated to give the title compound (40 mg,10%). The water phase was acidified with concentrated hydrochloric acidand extracted three times with DCM to give organic phase II. Thecombined organic phases II were dried and concentrated to give6-methoxy-pyridazine-3-carboxylic acid (LC-MS (M++1): 155) (230 mg,65%). A solution of 6-methoxy-pyridazine-3-carboxylic acid in thionylchloride (6 ml) was refluxed for 3 h. The reaction was cooled to ambienttemperature and evaporated to dryness. MeOH (10 ml) was added to theresidue and the solution was stirred on at rt. Saturated NaHCO₃ (aq) wasadded and the mixture was extracted three times with DCM. The combinedorganic phases were dried and concentrated to give the title compound(253 mg, 100%). LC-MS (M++1): 169. Step 4:4-Ethyl-5-(6-methoxy-pyridazin-3-yl)-2,4-dihydro-[1,2,4]triazole-3-thione:NaOMe (86 mg, 1.6 mmol) was added to a solution of6-methoxy-pyridazine-3-carboxylic acid methyl ester (210 mg, 1.25 mmol)and 4-ethyl-3-thiosemicarbazide (190 mg, 1.6 mmol) in MeOH (6 ml) andthe mixture was heated to 70° C. at 72 h. The reaction was cooled toambient temperature and evaporated to dryness. H₂O (10 ml) was added tothe residue and the mixture was acidified with concentrated hydrochloricacid and the title compound 35 mg (12%) was collected by filtration.LC-MS (M++1): 238.

Example 2174-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione

Step 1: 5-Methoxy-pyridine-2-carboxylic acid methyl ester:5-Methoxy-2-methyl-pyridine (700 mg, 5.69 mmol) was dissolved in H₂O (20ml) and heated to 80° C. KMnO₄ (4 g, 25.3 mmol) was added in portion tothe solution over 1 h. After stirring at 80° C. for 5 h the mixture wasfiltrated and the filtrate was washed with H₂O (60° C.). The combinedwater phase was concentrated. DMF (20 ml), K₂CO₃ (785 mg, 5.7 mmol)followed by MeI (540 ml, 8.6 mmol) was added to the remaining residueand the mixture was heated to 80° C. on. The reaction was cooled toambient temperature and H₂O was added and the mixture was extractedthree times with toluene. The combined organic phases were dried andconcentrated. Flashchromatography (SiO₂, Heptane/EtOAc 1:1) afforded 210mg (22%) of the title compound. 1H NMR (CDCl₃): d ppm 3.93 (s, 3H) 4.00(s, 3H) 7.23 (m, 1H) 8.13 (d, 1H) 8.40 (d, 1H). Step 2:4-Ethyl-5-(5-methoxy-pyridin-2-yl)-2,4-dihydro-[1,2,4]triazole-3-thione:NaOMe (4 ml, 4.0 mmol, 1M) was added to a solution of5-Methoxy-pyridine-2-carboxylic acid methyl ester (200 mg, 1.2 mmol),4-ethyl-3-thiosemicarbazide (145 mg, 1.2 mmol) in MeOH (10 ml) and themixture was heated to 70° C. on. The reaction was cooled to ambienttemperature and evaporated to dryness. H₂O (10 ml) was added to theresidue and the mixture was acidified with concentrated hydrochloricacid and the title compound 50 mg (18%) was collected by filtration.LC-MS (M++1): 237.

The following compounds were prepared analogously to example 10: ExampleNo. Name 218 5-Chloromethyl-3-phenyl-[1,2,4]oxadiazole 2195-Chloromethyl-3-(3-fluoro-phenyl)-[1,2,4]oxadiazole 2205-Chloromethyl-3-(2-fluoro-5-methyl-phenyl)- [1,2,4]oxadiazole 2215-Chloromethyl-3-thiophen-2-yl-[1,2,4]oxadiazole 2225-Chloromethyl-3-thiophen-3-yl-[1,2,4]oxadiazole 2233-(5-Chloromethyl-[1,2,4]oxadiazol-3-yl)-phenol 2245-Chloromethyl-3-o-tolyl-[1,2,4]oxadiazole 2255-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole 2265-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole

The following compounds were prepared analogously to example 16: ExampleNo. Name 227 3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile 2282-Chloro-4-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-pyridine 2293-Chloromethyl-5-(2,5-dimethyl-phenyl)-[1,2,4]oxadiazole 2303-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)- [1,2,4]oxadiazole 2313-Chloromethyl-5-(2,5-dichloro-phenyl)-[1,2,4]oxadiazole 2323-Chloromethyl-5-(2-fluoro-5-bromo-phenyl)- [1,2,4]oxadiazole 2333-Chloromethyl-5-(3-methyl-phenyl)-[1,2,4]oxadiazole 2343-Chloromethyl-5-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole 2353-Chloromethyl-5-(3-methylsulfanyl-phenyl)- [1,2,4]oxadiazole 2363-Chloromethyl-5-(3-cyclopropyl-phenyl)-[1,2,4]oxadiazole 2373-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic acidtert-butyl ester 2381-[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]- ethanone 2395-(5-Chloro-2-fluoro-phenyl)-3-chloromethyl- [1,2,4]oxadiazole 2402-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl-phenol

Example 2413-Chloromethyl-5-(2-chloro-5-methyl-phenyl)-[1,2,4]oxadiazole

2-Chloro-5-methyl-benzoic acid (1 g, 5.8 mmol) was treated with 5 mlthionyl chloride at reflux for two h. Excess thionyl chloride wasremoved under reduced pressure. The residue was added to a suspension of2-chloro-N-hydroxy-acetamidine (638 mg, 5.8 mmol) in dichloromethane (10ml) at room temperature. After stirring for 30 min, triethylamine (2.04ml, 14.6 mmol) was added and stirred for an additional h. The reactionmixture was diluted with ethyl acetate, washed with water and brine,dried over anhydrous sodium sulfate, filtered and concentrated. Flashcolumn chromatography using 10-20% ethyl acetate in hexanes afforded 460mg of the acyclic ester intermediate. DMF was added to this intermediateand then heated at 135° C. for 4 h to effect cyclization to oxadiazole.After cooling the reaction mixture was washed with water (3 times) andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.Purification by flash column chromatography on silica gel using 5% ethylacetate in hexanes afforded the title compound 160 mg (12% over 2 steps)as a white solid. m/z 244 (GCMS).

The following compounds were prepared analogously to Example 241:Example No. Name 242 3-Chloromethyl-5-(2,5-dichloro-thiophen-3-yl)-[1,2,4]oxadiazole 2433-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-benzonitrile 2443-Chloromethyl-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole 2453-Chloromethyl-5-(2-methyl-thiazol-4-yl)- [1,2,4]oxadiazole 2463-Chloromethyl-5-(4-fluoro-phenyl)-[1,2,4]oxadiazole 2475-(5-Bromo-2-fluoro-phenyl)-3-chloromethyl- [1,2,4]oxadiazole 2483-Chloromethyl-5-(4-methyl-thiophen-2-yl)- [1,2,4]oxadiazole 2495-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-thiophene-3- carbonitrile 2502-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-methyl- benzonitrile 2513-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-5-fluoro- benzonitrile 2523-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-4-fluoro- benzonitrile 2534-Chloro-2-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenol 2543-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole 2553-(1-Chloro-ethyl)-5-(3-fluoro-phenyl)-[1,2,4]oxadiazole 2563-(1-Chloro-ethyl)-5-(5-chloro-2-fluoro-phenyl)- [1,2,4]oxadiazole

Example 257 [3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol

3-Hydroxymethylbenzoic acid, described in Reed, G. A.; Dimmel, D. R.;Malcolm, E. W. J. Org. Chem. 1993, 58 (23), 6372-6376, (175 mg, 1.15mmol), 2-chloro-N-hydroxy-acetamidine (125 mg, 1.15 mmol) and HBTU wasdissolved in anhydrous DMF (4 ml). Triethylamine (0.48 ml, 3.5 mmol) wasadded and the reaction was stirred at ambient temperature over night.The crude product was partitioned between dichloromethane and NaHCO₃(aq), the organic phase was dried (MgSO₄) and the dichloromethane wasremoved in vacuo. The resulting DMF-solution was heated at 120° C. overnight. The reaction mixture was concentrated in vacuo and the titlecompound (64 mg, 25%) was isolated by flash chromatography using 25-50%ethyl acetate in heptane. 1H NMR (CDCl₃), δ (ppm): 8.15 (s, 1H), 8.06(d, 1H), 7.62 (d, 1H), 7.53 (t, 1H); 4.80 (d, 2H), 4.66 (s, 1H); 1.99(br. t, 1H).

The following compounds were prepared analogously to Example 257:Example No. Name 2583-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-[1,2,4]oxadiazole 259 3-Chloromethyl-5-furan-3-yl-[1,2,4]oxadiazole 2603-Chloromethyl-5-(5-chloro-thiophen-2-yl)- [1,2,4]oxadiazole

Example 261 1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol

Step 1:1-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-1H-benzotriazole:2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (109 mg, 0.45mmol), hydroxybenzotriazole (76.4 mg, 0.56 mmol) and potassium iodide(23.0 mg, 0.14 mmol) were dissolved in DMF (2.5 ml), followed by theaddition of potassium carbonate (74.0 mg, 0.53 mmol). After stirringunder argon at ambient temperatures for 24 h the reaction mixture wasdiluted with ethyl acetate and washed with 2N ammonium chloridesolution. After reextraction of the aqueous layer with ethyl acetate,the combined organic layers were washed with brine and evaporated todryness. Column chromatography over 12 g silica using heptane/ethylacetate=4/1 gave after drying in vacuo the title compound (129 mg, 84%).1H NMR (CDCl₃), δ (ppm): 7.94 (d, 1H), 7.82 (m, 1H), 7.76 (m, 1H), 7.46(m, 1H), 7.39-7.27 (m, 4H), 5.98 (q, 1H), 2.04 (d, 3H). Step 2:1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethanol:1-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethoxy}-1H-benzotriazole(58.4 mg, 0.17 mmol) was dissolved under argon in dry THF (3 ml). Tothis mixture a 0.1 molar solution of samarium diiodide in THF (5 ml, 0.5mmol) was slowly added over 20 min. After stirring for 80 min additionalsamarium diode solution (4 ml, 0.4 mmol) was added during 5 min. Thereaction mixture was quenched after further 15 min of stirring withaqueous Na₂S₂O₃, diluted with diethyl ether and washed with 1 molareaqueous hydrochloric acid, dried over sodium sulfate and evaporated todryness. After drying in vacuo crude title compound was obtained (36.0mg, 92%) which was used in the next step without further purification.1H NMR (CDCl₃), δ (ppm): 7.98-7.75 (m, 2H), 7.50-7.38 (m, 2H), 5.25 (q,1H), 1.74 (d, 3H).

The following compounds were prepared analogously to Example 261:Example No. Name 262[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]- methanol

Example 263 1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol

To a solution of 3.19 g (30.6 mmol) 2,N-dihydroxy-propionamidine in 25ml pyridine was added 4.3 ml (33.7 mmol) 3-chloro-benzoyl chloride at 0°C. Cooling was removed and the mixture was stirred at room temperaturefor 25 min and at reflux for 25 min. After cooling the mixture waspoured into water and extracted twice with CH₂Cl₂. The organic phase wasdried and concentrated. Recrystallization from heptane/EtOAc afforded4.12 g (60%) of a white solid. 1H NMR (CDCl₃), d (ppm): 1.68 (d, 3H)2.67 (m, 1H) 5.09 (m, 1H) 7.46 (t, 1H) 7.56 (d, 1H) 8.01 (d, 1H) 8.13(s, 1H).

Example 264 [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol

Step 1:N-{4-[(Z)-{[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]methylene}(oxido)amino]phenyl}-N,N-dimethylamine:The title compound was synthesized according to the method described inPalazzo et al. J. Heterocycl. Chem. (1979) 16:1469.1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride(1.81 g, 5.87 mmol) was dissolved in water (20 ml). To this solution,4-nitroso-N,N-dimethylanilin (0.88 g, 5.86 mmol) dissolved in ethanol(50 ml) was added, followed by slow addition of 1 molar aq. sodiumhydroxide (5.9 ml, 5.9 mmol) over a 3 min period. After 1 h the formedprecipitate was filtered, washed with water and air-dried to give thetitle compound (2.08 g, wet) which was used immediately in the next stepMS (ESI) m/z 344 (M+1). Step 2:[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanediol:N-{4-[(Z)-{[5-(3-Chlorophenyl)-1,2,4-oxadiazol-3-yl]methylene}(oxido)amino]phenyl}-N,N-dimethylamine(2.08 g wet) was suspended in diethyl ether (30 ml), followed by theaddition of 1 molar aqueous hydrochloric acid. The mixture was stirredvigorously for 20 min, transferred to a separation funnel and dilutedwith diethyl ether and 1 molar aqueous hydrochloric acid. Afterextraction, the aqueous layer was extracted two more times with diethylether. Combining the organic layers, drying over magnesium sulfate,followed by evaporation to dryness and drying in vacuo gave the titlecompound as crude (0.56 g, 42% from1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridiniumchloride). MS (ESI) m/z 227 (M+1). Step 3:[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol: Step 3:[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol:1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-pyridinium chloride(99.3 mg, 0.44 mmol) was dissolved in methanol (4 ml) followed by theaddition of sodium borohydride (32 mg, 0.84 mmol). More sodiumborohydride was added after 2 h and the reaction was allowed to run overnight. The reaction mixture was diluted with dichloromethane and aq.ammonium chloride and stirred vigorously. After separation of the layersand washing of the organic layer with brine, followed by evaporation todryness, crude product was obtained. This was purified by flashchromatography using heptane/ethyl acetate which gave the title compound(32.0 mg, 32%). 1H NMR (CDCl₃), δ (ppm): 8.11 (s, 1H), 8.00 (apparent d,1H), 7.56 (apparent d, 1H), 7.46 (apparent t, 1H), 4.87 (d, 2H), 2.91(t, 1H).

Example 2652-Chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole

2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at120° C. for 30 min. The reaction mixture was place directly onto a flashcolumn (silica gel) and purified by using 0-5% ethyl acetate in hexanesto afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole(284.5 mg, 66%). 1H NMR (CDCl₃)

(ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s,3H).

The following compounds were prepared analogously to Example 265:Example No. Name 2662-Chloromethyl-5-(3-chloro-phenyl)-[1,3,4]oxadiazole 2674-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-2-methyl- pyridine 2682-Chloromethyl-5-m-tolyl-[1,3,4]oxadiazole 2693-(5-Chloromethyl-[1,3,4]oxadiazol-2-yl)-benzonitrile 2702-Chloro-4-(5-chloromethyl-[1,3,4]oxadiazol-2-yl)- pyridine 2712-(5-Chloro-2-fluoro-phenyl)-5-chloromethyl- [1,3,4]oxadiazole

Example 272 2-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole

3-Chloro-benzoic acid hydrazide (170 mg, 1 mmol) and2-bromo-1,1,1-triethoxypropane (1 ml) were heated in a sealed vial at120° C. for 10 min. The reaction mixture was place directly onto a flashcolumn (silica gel) and purified using 0-50% dichloromethane in hexanes.The product was re-purified by flash column chromatography using amixture of ethyl acetate:hexanes:dichloromethane (1:19:20) to afford2-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (93 mg, 32%,colorless oil). 1H NMR (CDCl₃)

(ppm): 8.09 (t, 1H), 7.99 (t, 1H), 7.55 (m, 3H), 5.30 (m, 1H), 2.21 (q,3H).

The following compounds were prepared analogously to Example 272:Example No. Name 273 2-(1-Bromo-ethyl)-5-(5-chloro-2-fluoro-phenyl)-[1,3,4]oxadiazole 2744-[5-(1-Bromo-ethyl)-[1,3,4]oxadiazol-2-yl]-2-methyl- pyridine 2752-(1-Bromo-ethyl)-5-(2-fluoro-5-methyl-phenyl)- [1,3,4]oxadiazole 2762-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole

Example 277 3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole

A solution of 396 mg (2.22 mmol) N-bromosuccinimid in 2 ml THF was addeddropwise to a solution of 583 mg (2.22 mmol) triphenylphosphine in 2 mlTHF at 0° C. After stirring for 20 min 416 mg (1.85 mmol)1-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethanol in 2 ml THF wasadded. Stirring was continued overnight at room temperature before thesolvent was removed under reduced pressure. Flash chromatography(heptane/EtOAc 6:1) afforded 168 mg (32%). 1H NMR (CDCl₃), d (ppm): 2.12(d, 3H) 5.21 (q, 1H) 7.47 (t, 1H) 7.57 (m, 1H) 8.03 (d, 1H) 8.15 (s,1H).

Example 278 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol

Step 14-(3-Chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester: Sodiumhydride (60% oil dispersion, 1.24 g, 31.1 mmol) was added in portions toa solution of 3-chloroacetophenone (4.0 g, 25.9 mmol) and diethyloxalate (4.54 g, 31.1 mmol) in DMF (32 ml) at 0° C. The mixture stirredat room temperature for 1 h and was then heated at 80° C. for a half anh. After cooling, the mixture was treated with 3N HCl and then dilutedwith ethyl acetate. The organic layer was washed with water (3×) andsaturated brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The resulting residue was then purified by flash columnchromatography on silica using 0-10% ethyl acetate in hexanes to affordof 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (4.43 g, 67%,yellow solid). 1H NMR (CDCl₃) d (ppm): 15.12 (br s, 1H), 7.98 (s, 1H),7.88 (d, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.05 (s, 1H), 4.39 (m, 2H),1.41 (m, 3H). Step 2: 5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acidethyl ester: A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acidethyl ester (3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g,35.4 mmol) in methanol (60 ml) was heated at 80° C. for 4 h. Aftercooling, the mixture was filtered and washed with cold methanol toafford 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (2.0g, 71%, white solid). 1H NMR (CDCl₃) d (ppm): 7.82 (s, 1H), 7.72 (m,1H), 7.47 (m, 2H), 4.03 (s, 3H). Mixture of both methyl and ethyl ester(mostly methyl). Step 3: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone:In a screw cap vial equipped with stir bar added methyl magnesium iodide(3M in diethyl ether) (0.79 ml, 2.38 mmol), toluene (1 ml),tetrahydrofuran (0.39 ml, 4.77 mmol) and triethylamine (1 ml, 7.15mmol). Cooled the solution down to 0° C. and to it added solution of5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (300 mg,1.19 mmol) in toluene (5 ml). Left the resulting mixture stirring at 0°C. for 5 h. Reaction mixture was quenched with 1N hydrochloric acid(aqueous, 6.5 ml, 6.5 mmol), diluted with toluene (35 ml), sequentiallywashed with water (50 ml), saturated sodium bicarbonate (aqueous, 30ml), water (50 ml) and brine (30 ml). The organic phase wasconcentrated, in-vacuo. The isolated residue was dissolved in methanol(8 ml) and 20% potassium hydroxide (aqueous, 1 ml). The mixture wasstirred at 45° C. for 30 min. At this point the mixture wasconcentrated, in-vacuo. The isolated residue was dissolved in toluene(60 ml), sequentially washed with water (50 ml), saturated sodiumbicarbonate (aqueous, 50 ml) and water (50 ml). The organic phase wasconcentrated, in-vacuo. The crude residue was purified on silica gelusing 2% ethyl acetate in hexanes to isolate the desired compound as awhite solid (156 mg, 60%). 1H-NMR (CDCl₃), d (ppm): 7.77 (m 1H), 7.66(m, 1H), 7.42 (m, 2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 4:1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vialequipped with stir bar added1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol),sodium borohydride (34 mg, 0.90 mmol) and methanol (3 ml). Left theresulting mixture stirring at room temperature for 3 h. Reaction wasquenched with water (30 ml) and brine (30 ml), extracted withdichloromethane (3×30 ml). Combined organic phase was dried (sodiumsulfate), filtered and concentrated, in-vacuo to isolate1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol as a white solid (110 mg).1H-NMR (CDCl₃), d (ppm): 7.69 (m, 1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59(s, 1H), 5.07 (q, 1H), 3.45 (bs, 1H), 1.58 (d, 3H).

The following compound was prepared analogously to Example 278: ExampleNo. Name 279 1-[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-ethanol

The following compounds were prepared analogously to5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester (step 2 inthe synthesis of Example 279): Example No. Name 2805-(2-Fluoro-5-methyl-phenyl)-isoxazole-3-carboxylic acid methyl ester281 5-Thiophen-3-yl-isoxazole-3-carboxylic acid methyl ester 2825-Phenyl-isoxazole-3-carboxylic acid methyl ester 2835-(3-Chloro-phenyl)-4-methyl-isoxazole-3-carboxylic acid ethyl ester 2845-(5-Chloro-thiophen-3-yl)-isoxazole-3-carboxylic acid methyl ester

Example 285 [5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol

Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added to asolution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester(2.0 g, 8.4) in THF (100 ml) at room temperature. After 1 h, thereaction mixture was quenched with water and then extracted with ethylacetate. The organic layer was washed with water and saturated brine,dried over anhydrous sodium sulfate, filtered, and concentrated. Theresulting residue was then purified by flash column chromatography using15-40% ethyl acetate in hexane to afford[5-(3-chloro-phenyl)-isoxazol-3-yl]-methanol (1.32 g, 75%, yellowsolid). 1H NMR (CDCl₃) d (ppm): 7.78 (s, 1H), 7.68 (m, 1H), 7.43 (m,2H), 6.63 (s, 1H), 4.84 (d, 2H), 2.23 (t, 1H).

The following compounds were prepared analogously to Example 285:Example No. Name 286 [2-(3-Chloro-phenyl)-oxazol-4-yl]-methanol 287[3-(3-Chloro-phenyl)-isoxazol-5-yl]-methanol 2885-(Thiophen-3-yl-isoxazol-3-yl)methanol 289[5-(2-Fluoro-5-methyl-phenyl)-isoxazol-3-yl]-methanol 290(5-Phenyl-isoxazol-3-yl)-methanol 291[5-(3-Chloro-phenyl)-4-methyl-isoxazol-3-yl]-methanol 292[5-(5-Chloro-thiophen-3-yl)-isoxazol-3-yl)]-methanol

Example 293 Methanesulfonic acid1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethyl ester

In a screw cap vial equipped with stir bar was added1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (110 mg, 0.49 mmol),dichloromethane (3 ml) and triethylamine (0.34 ml, 2.46 mmol). Cooledthe mixture down to 0° C. and to it added methane sulfonyl chloride(0.08 ml, 0.98 mmol). Left the reaction mixture stirring at roomtemperature for 30 min. Reaction was quenched with saturated sodiumbicarbonate (aqueous, 40 ml) and extracted with dichloromethane (3×30ml). Combined organic phase was washed with brine (40 ml), dried (sodiumsulfate), filtered and concentrated, in-vacuo to isolate the desiredcompound as brown oil.

The following compounds were prepared analogously to Example 293:Example No. Name 294 Methanesulfonic acid 2-(3-chloro-phenyl)-oxazol-4-ylmethyl ester 295 Methanesulfonic acid 3-(3-chloro-phenyl)-isoazol-5-ylmethyl ester 296 Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)-isoxazol-3-ylmethyl ester 297 Methanesulfonicacid-phenyl)-isoxazol-5-yl]-ethyl ester 298 Methanesulfonic acid5-(5-chloro-2-fluoro-phenyl)- isoxazol-3-ylmethyl ester 299Methanesulfonic acid 5-(3-chloro-phenyl)-isoxazol- 3-ylmethyl ester 300Methanesulfonic acid 5-thiophen-3-yl-isoxazol-3-ylmethyl ester 301Methanesulfonic acid 5-(2-fluoro-5-methyl-phenyl)- isoxazol-3-ylmethylester 302 Methanesulfonic acid 5-phenyl-isoxazol-3-ylmethyl ester 303Methanesulfonic acid 5-(3-chloro-phenyl)-4-methyl- isoxazol-3-ylmethylester 304 Methanesulfonic acid 5-(5-chloro-thiophen-3-yl)-isoxazol-3-ylmethyl ester 305 Methanesulfonic acid1-[5-(2-fluoro-5-methyl-phenyl)- isoxazol-3-yl]-ethyl ester 306Methanesulfonic acid 1-[5-(5-chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethyl ester

Example 307 Methanesulfonic acid4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester

Sulfuryl chloride (1 ml) was added to methanesulfonic acid5-(3-chloro-phenyl)-isoxazol-3-ylmethyl ester (200 mg, 0.70 mmol) andthen stirred at 60° C. overnight. The reaction mixture was diluted withdichloromethane, washed saturated sodium bicarbonate, dried overanhydrous sodium sulfate, filtered and concentrated to affordmethanesulfonic acid 4-chloro-5-(3-chloro-phenyl)-isoxazol-3-ylmethylester (219 mg, 97%, light brown solid). 1H NMR (CDCl₃) d (ppm): 8.07 (m,1H), 7.92 (m, 1H), 7.50 (m, 2H), 5.38 (s, 2H), 3.16 (s, 3H).

Example 308 3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methyl ester

Step 1: 3-Chloro-N-hydroxy-benzamidine: A solution of3-chlorobenzaldehyde (3.35 ml, 0.030 mmol) in ethanol (40 ml) was addedto a solution of hydroxylamine hydrochloride (2.47 g, 0.036 mmol) andsodium hydroxide (1.42 g, 0.036) in water (20 ml) at room temperatureand then heated at 90° C. for 24 h. After cooling, the reaction mixturewas concentrated, the residue diluted with water and then theprecipitate was filtered and dried to afford3-chloro-N-hydroxy-benzamidine (1.13 g, 93%). 1H NMR (CDCl₃) d (ppm):8.11 (s, 1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H).Step 2: 3-Chloro-N-hydroxy-benzimidoyl chloride: N-chlorosuccinimide(858 mg, 6.4 mmol) was added to a solution of3-chloro-N-hydroxy-benzamidine (1 g, 6.4 mmol) at room temperature andstirred for 1 h. The reaction mixture was diluted with diethyl ether andthen washed with water (3×), dried over anhydrous magnesium sulfate,filtered, and concentrated to afford the titled compound (1.13 g, 93%).1H NMR (CDCl₃) d (ppm): 8.03 (s, 1H), 7.87 (m, 1H), 7.76 (m, 1H), 7.43(m, 1H): Step 3: 3-(3-Chloro-phenyl)-isoxazole-5-carboxylic acid methylester: Triethyl amine (0.73 ml, 5.3 mmol) was added drop-wise to asolution of 3-chloro-N-hydroxy-benzimidoyl chloride (1.0 g, 5.3 mmol)and methyl propiolate (2.2 ml, 25.3 mmol) in an ice-bath. The reactionmixture was warmed to room temperature and left to stir overnight. Afterdiluting the reaction with dichloromethane, the organic layer was washedwith water and saturated brine, dried over anhydrous sodium sulfate,filtered, and concentrated. Purification by flash column chromatographyeluted with 50% hexanes in ethyl acetate and then recrystallization withmethanol afforded 3-(3-chloro-phenyl)-isoxazole-5-carboxylic acid methylester (635 mg, 51%, white solid). 1H NMR (CDCl₃) d (ppm): 7.86 (m, 1H),7.74 (m, 1H), 7.46 (2H), 7.2 (s, 1H), 4.05 (s, 3H).

Example 309 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole

Step 1 5-(3-Chloro-phenyl)-2-methyl-oxazole: To a solution of T1(OAc)3(4.2 g, 11.1 mmol) in acetonitrile (80 ml), trifluoromethanesulfuricacid (5 g, 33.3 mmol) was added dropwise at room temperature and stirredfor 15 min. The reaction mixture was then heated to 80° C. and1-(3-chloro-phenyl)-ethanone (1.14 g, 7.4 mmol) in acetonitrile (40 ml)was added. After one h, the reaction was quenched with dichloromethaneand saturated sodium bicarbonate. The organic layer was dried, purifiedby column chromatography with 5˜19% ethyl acetate in hexanes to give 1.2(83.9%) g of 5-(3-chloro-phenyl)-2-methyl-oxazole as yellow oil. 1H-NMR(CDCl₃) d (ppm): 7.60 (s, 1H), 7.48 (d, 1H), 7.29 (m, 2H), 7.23 (s, 1H)and 2.34 (s, 3H). Step 2: 2-Bromomethyl-5-(3-chloro-phenyl)-oxazole:5-(3-chloro-phenyl)-2-methyl-oxazole (580 mg, 3 mmol) was mixed with NBS(531 mg, 3 mmol) and BPOA (36.3 mg, 0.15 mmol) in CCl₄ at roomtemperature. The reaction mixture was heated at 75° C. for 2 h and thenquenched with water and dichloromethane. The organic layer was dried,concentrated, purified by column chromatography with 2˜5% ethyl acetatein hexanes to give 562 mg (68.3%) of2-bromomethyl-5-(3-chloro-phenyl)-oxazole as yellow oil. 1H-NMR (CDCl₃)d (ppm): 7.67 (s, 1H), 7.54 (d, 1H), 7.35 (m, 3H) and 4.56 (s, 2H).

Example 310 2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester

To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol), serinemethylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9mmol) in DMF (100 ml) was added N-methylmorpholine (NMM) (7.0 ml, 63.8mmol) and EDCI (4.97 g, 31.9 mmol) at 0° C. The mixture was allowed towarm to room temperature and stirred for 18 h. The mixture was dilutedwith ethyl acetate (300 ml) and then washed with water (3×250 ml)followed by brine. The organic extract was dried over Na₂SO₄ (anhydrous)and then concentrated in vacuo giving2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g,93%) of a pale yellow solid. 1H NMR (CDCl₃) d (ppm): 7.78 (s, 1H), 7.66(d, 1H), 7.45, (dd, 1H), 7.34 (t, 1H), 7.25 (br, d, 1H), 4.82 (m, 1H),4.08 (m, 2H), 3.79 (s, 3H), 3.19 (br, t, 1H).

To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acidmethyl ester (7.2 g, 29.6 mmol) in CH₂Cl₂ at −20° C. was added dropwiseDe-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for30 min, BrCCl₃ (3.6 g, 18.1 mmol) was added dropwise followed by DBU(2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h adthen quenched with saturated NaHCO₃ followed by extraction with ethylacetate. The organic extract as then washed with brine and dried overNa₂SO₄ (anhydrous). Purification was performed by flash columnchromatography on silica gel using ethyl acetate in hexanes as eluant toafford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1g, 59%) as a yellow solid. 1H NMR (CDCl₃) d (ppm): 8.30 (s, 1H), 8.12(d, 1H), 7.98 (dd, 1H), 7.45 (m, 2H), 3.96 (s, 3H).

Example 311 2-(3-Chloro-phenyl)-oxazole-4-carboxylic acid methyl ester

To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol), serinemethylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9mmol) in DMF (100 ml) was added N-methylmorpholine (NMM) (7.0 ml, 63.8mmol) and EDCI (4.97 g, 31.9 mmol) at 0° C. The mixture was allowed towarm to room temperature and stirred for 18 h. The mixture was dilutedwith ethyl acetate (300 ml) and then washed with water (3×250 ml)followed by brine. The organic extract was dried over Na₂SO₄ (anhydrous)and then concentrated in vacuo giving2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g,93%) of a pale yellow solid. 1H NMR (CDCl₃) d (ppm): 7.78 (s, 1H), 7.66(d, 1H), 7.45, (dd, 1H), 7.34 (t, 1H), 7.25 (br, d, 1H), 4.82 (m, 1H),4.08 (m, 2H), 3.79 (s, 3H), 3.19 (br, t, 1H).

To a solution of 2-(3-chloro-benzoylamino)-3-hydroxy-propionic acidmethyl ester (7.2 g, 29.6 mmol) in CH₂Cl₂ at −20° C. was added dropwiseDe-oxofluor (7.2 g, 32.6 mmol). After stirring at this temperature for30 min, BrCCl₃ (3.6 g, 18.1 mmol) was added dropwise followed by DBU(2.79 g, 18.1 mmol). The mixture was then stirred at 2-3° C. for 8 h adthen quenched with saturated NaHCO₃ followed by extraction with ethylacetate. The organic extract as then washed with brine and dried overNa₂SO₄ (anhydrous). Purification was performed by flash columnchromatography on silica gel using ethyl acetate in hexanes as eluant toafford 2-(3-chloro-phenyl)-oxazole-4-carboxylic acid methyl ester (4.1g, 59%) as a yellow solid. 1H NMR (CDCl₃) d (ppm): 8.30 (s, 1H), 8.12(d, 1H), 7.98 (dd, 1H), 7.45 (m, 2H), 3.96 (s, 3H).

Example 312 1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol

Step 1: 5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde: In a 50ml round bottom flask equipped with stir bar and drying tube added5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester(0.78 g, 2.89 mmol) and dichloromethane (10 ml). Cooled the solutiondown to −78° C. and to this stirred solution added diisobutylaluminumhydride (1M hexanes, 5.3 ml, 5.3 mmol). The resulting mixture was leftstirring at −78° C. for 3 h. Reaction was quenched using sodium sulfatedecahydrate. The resulting mixture was stirred at 63° C. for 15 minafter which it was filtered through a celite pad. The filterate wasconcentrated in-vacuo to isolate an off-white solid, which wastriturated with hexanes to isolate the title compound as a white solid(0.55 g, 84%). 1H-NMR (CDCl₃), d (ppm): 10.2 (s, 1H), 7.99 (m, 1H), 7.44(m, 1H), 7.20 (m, 1H), 7.10 (d, 1H). Step 2:1-[5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-ethanol: In a 50 ml roundbottom flask equipped with stir bar added5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carbaldehyde (0.55 g, 2.42mmol) and tetrahydrofuran (6 ml). Cooled the mixture down to 0° C. andto it added methyl magnesium iodide (3M in diethyl ether, 3.23 ml, 9.67mmol). The resulting mixture was left stirring at 0° C. for 3 h.Reaction mixture was quenched with hydrochloric acid (1N, aqueous, 10ml), extracted with diethyl ether (3×50 ml). Combined organic phase waswashed with water (50 ml), brine (50 ml), dried (sodium sulfate),filtered and concentrated in-vacuo. The crude residue was purified onsilica gel using 10% ethyl acetate in hexanes to isolate the desiredcompound as clear oil (179 mg, 31%).

Example 313 1-[3-(3-Chloro-phenyl)-isoxazol-5-yl]-ethanol

3-Chloro-benzohydroximoyl chloride (e.g. Kim, Jae Nyoung; Ryu, Eung K;J. Org. Chem. (1992), 57(24), 6649-50) (2.84 g, 14.8 mmol) was suspendedin benzene (50 ml) and cooled to 0° C. 3-Butyn-2-ol (2.10 g, 29.9 mmol)and triethylamine (1.89 ml, 26.7 mmol) were added. The mixture washeated to 60° C. for 1.5 hours, cooled and diluted with benzene and 1Naqueous hydrochloric acid. After stirring, the separated benzene layerwas evaporated to dryness and the crude purified via flashchromatography over silica using heptane/ethyl acetate=5/1 giving afterdrying in vacuo the title compound (0.49 g, 15%). 1H NMR (CDCl₃), δ(ppm): 1.64 (d, 3H), 5.07 (dq, 1H), 6.50 (s, 1H), 7.40 (m, 2H), 7.68 (m,1H), 7.79 (m, 1H)

Example 314 [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol

Step 1: (5-Chloro-2-fluoro-phenylethynyl)-trimethyl-silane: In a 250 mlround bottom flask equipped with a stir bar and reflux condenser added4-chloro-2-bromo-1-fluoro-benzene (5 g, 23.9 mmol), triphenylphosphine(250 mg, 0.10 mmol), (trimethylsilyl)acetylene (5.2 ml, 36.5 mmol) andtriethylamine (60 ml). The reaction mixture was purged with argon,followed by addition of palladium (II) acetate (108 mg, 0.05 mmol). Theresulting mixture was left stirring at reflux under argon, overnight.The reaction mixture was filtered through a pad of celite using ethylacetate and the filterate was concentrated in-vacuo. The isolatedresidue was absorbed on silica gel and filtered using hexanes. Thefilterate was concentrated in-vacuo to isolate the title compound asbrown oil (5.42 g). Step 2: 4-Chloro-2-ethynyl-1-fluoro-benzene: In a250 ml round bottom flask equipped with stir bar added(5-chloro-2-fluoro-phenylethynyl)-trimethyl-silane (5.42 g, 23.9 mmol),potassium carbonate (16.5 g, 120 mmol) and methanol (60 ml). Thereaction mixture was left stirring at room temperature for 1 h. Dilutedthe reaction mixture with hexanes (200 ml) and washed with water (250ml). The aqueous phase was extracted with hexanes (2×100 ml). Combinedorganic phase was washed with brine (200 ml), dried (sodium sulfate),filtered and concentrated in-vacuo to isolate the desired compound asbrown oil (3.56 g). 1H-NMR (CDCl₃), d (ppm): 7.47 (dd, 1H), 7.30 (m,1H), 7.05 (t, 1H), 3.36 (s, 1H). Step 3: Chloro-hydroxyimino-acetic acidethyl ester: In 1 L round bottom flask equipped with stir bar addedamino-acetic acid ethyl ester hydrochloride (20 g, 143 mmol) and water(30 ml). The solution was cooled down to 0° C. followed by sequentialaddition of concentrated hydrochloric acid (11.8 ml, 143 mmol) anddropwise addition of sodium nitrite (9.89 g, 143 mmol) solution in water(15 ml). After 10 min added another equivalent each of concentratedhydrochloric acid and sodium nitrite solution in water. The reactionmixture was left stirring at 0° C. for 1 h. Reaction mixture wasextracted with ether (4×100 ml). Combined organic phase was dried(sodium sulfate), filtered and concentrated in-vacuo to isolate a lemonyellow solid. The solid was recrystallized from hexanes to isolate awhite solid (11 g, 51%). 1H-NMR (CDCl₃), d (ppm): 9.98 (bs, 1H), 4.40(q, 2H), 1.38 (t, 3H). Step 4:5-(5-Chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester: Ina 250 ml round bottom flask equipped with stir bar added4-chloro-2-ethynyl-1-fluoro-benzene (2 g, 12.9 mmol),chloro-hydroxyimino-acetic acid ethyl ester (3.92 g, 25.9 mmol), sodiumbicarbonate (7.07 g, 84.1 mmol) and toluene (50 ml). Reaction mixturewas left stirring at room temperature for 48 h, after which it wasconcentrated in-vacuo. Residue was taken up in ethyl acetate (200 ml),sequentially washed with water (150 ml), brine (150 ml), dried (sodiumsulfate), filtered and concentrated in-vacuo. The crude residue waspurified on silica gel using 3% acetone in hexanes to isolate the titlecompound as an off-white solid (1.56 g). 1H-NMR (CDCl₃), d (ppm): 8.00(dd, 1H), 7.43 (m, 1H), 7.18 (m, 2H), 4.51 (q, 2H), 1.47 (t, 3H). Step5: [5-(5-Chloro-2-fluoro-phenyl)-isoxazol-3-yl]-methanol: In a 50 mlround bottom flask equipped with stir bar and drying tube added5-(5-chloro-2-fluoro-phenyl)-isoxazole-3-carboxylic acid ethyl ester(0.78 g, 2.89 mmol) and tetrahydrofuran (10 ml). To this stirredsolution added solution of lithium aluminum hydride (0.12 g, 2.89 mmol)in tetrahydrofuran (2 ml). The resulting mixture was left stirring atroom temperature for 1 h. Reaction was quenched using sodium sulfatedecahydrate. The resulting mixture was stirred at 63° C. for 15 minafter which it was filtered through a celite pad. The filterate wasconcentrated in-vacuo to isolate the title compound as yellow solid(0.65 g, 99%). 1H-NMR (CDCl₃), d (ppm): 7.73 (dd, 1H), 7.27 (m, 1H),7.24 (t, 1H), 6.73 (d, 1H), 4.77 (s, 2H), 4.45 (bs, 1H).

Example 315 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acidhydrazide

Step 1: 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid:3-Chloro-benzoic acid hydrazide (3.4 g, 20 mmol) and succinic anhydride(2. g, 20 mmol) was mixed in ethyl acetate (50 ml) at room temperaturefor 15 min. The reaction mixture was diluted with ether and theprecipitate was filtered to give 5.1 g of4-[N′-(3-chloro-benzoyl)-hydrazino]-4-oxo-butyric acid. 1H-NMR(CDCl₃+DMSO-d6) d (ppm): 10.01 (s, 1H), 9.53 (s, 1H), 7.68 (s, 1H), 7.55(d, 1H), 7.21 (d, 1H), 7.12 (t, 1H) and 2.35 (m, 4H). This solid wasmixed with conc. H₂SO₄ and stirred at room temperature for 45 min andthe reaction mixture was carefully added to crashed ice (400 g). Theprecipitate was filtered to give 4.07 g (80.6%) of3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid as whitesolid. 1H-NMR (DMSO-d6) d (ppm): 12.4 (w, 1H), 7.96 (s, 1H), 7.91 (d,1H), 7.71 (d, 1H), 7.63 (t, 1H), 3.15 (t, 2H) and 2.82 (t, 2H). Step 2:3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid hydrazide:3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid (2.52 g, 10mmol) was mixed with iodomethane (5.68 g, 40 mmol) and K₂CO₃ (5.52 g, 40mmol) in DMF (25 ml) at room temperature overnight. The reaction mixturewas diluted with ethyl acetate and washed with water 3 times, dried withMgSO₄ and concentrated to give 2.57 g of3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acid methylester. The methyl ester (2.54 g, 9.52 mmol) was mixed with 98% hydrazinehydrate (4.76 g, 95.2 mmol) in methanol (10 ml) for an h. The reactionmixture was concentrated, diluted with water, filtered to give 2.17 g(81.4%) of 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-propionic acidhydrazide as white solid. 1H-NMR (CDCl₃+DMSO-d6) d (ppm): 8.75 (w, 1H),7.91 (s, 1H), 7.82 (d, 1H), 7.42 (m, 2H), 3.45 (w, 2H), 3.19 (t, 2H) and2.68 (t, 2H).

Example 316 3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acidhydrazide

Step 1: 2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonicacid dimethyl ester:2-(1-Chloro-ethyl)-5-(3-chloro-phenyl)-[1,3,4]oxadiazole (331 mg, 1.36mmol) was mixed with dimethyl malonate (360 mg, 2/76 mmol) and DBU (207mg, 1.36 mmol) in acetonitrile (3 ml) at 70° C. overnight. The reactionmixture was dilute with dichloromethane and washed with water. Theorganic layer was dried and concentrated. The residue was purified with5˜20% ethyl acetate in hexanes to give 357 mg (74.3%)2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic aciddimethyl ester as white solid. 1H-NMR (CDCl₃) d (ppm): 8.03 (s, 1H),7.95 (d, 1H), 7.53 (d, 1H), 7.47 (t, 1H), 4.06 (d, 1H), 3.95 (m, 1H),3.84 (s, 3H), 3.74 (s, 3H) and 1.51 (d, 3H). Step 2:3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester:2-{1-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-ethyl}-malonic aciddimethyl ester (352.8 mg, 1.0 mmol) was mixed with sodium chloride (76.3mg, 1.3 mmol) and a drop of water in DMSO (1.5 ml) at 175° C. for an h.The reaction mixture was diluted with water and extracted withdichloromethane. The organic layer was washed with water andconcentrated. The residue was purified with column chromatography with10˜20% ethyl acetate in hexanes to give 215 mg(76.8%)3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methylester as clear oil. 1H-NMR (CDCl₃) d (ppm): 8.03 (s, 1H), 7.94 (d, 1H),7.53 (d, 1H), 7.45 (t, 1H), 3.73 (s, 3H), 3.67 (m, 1H), 3.05 (dd, 1H),2.73 (dd, 1H) and 1.50 (d, 3H). Step 3:3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid hydrazide:3-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid hydrazide(146 mg, %) was obtained from3-[5-(3-chloro-phenyl)-[1,3,4]oxadiazol-2-yl]-butyric acid methyl ester(215 mg, 0.766 mmol) reacted with hydrazine hydrate (0.74 ml) inmethanol (3 ml) at room temperature for 2.5 h. 1H-NMR (CDCl₃) d (ppm):8.03 (s, 1H), 7.94 (d, 1H), 7.53 (d, 1H), 7.46 (t, 1H), 7.23 (w, 1H),3.93 (w, 2H), 3.71 (m, 1H), 2.90 (dd, 1H), 2.57 (dd, 1H) and 1.50 (d,3H).

Example 317 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidicacid ethyl ester hydrochloride

Step 1: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid (1.6 g,6.33 mmol) was reacted with SOCl₂ (10 ml) at room temperature overnight.The reaction mixture was concentrated by vacuum. The residue was mixedwith THF (20 ml) and quenched with 28% NH₃.H₂O (5 ml) at 0° C. Afterbeing stirred for 2 h, the reaction mixture was dilute withdichloromethane and washed with water and brine. The organic layer wasdried, concentrate and triturated with hexanes to give 1.21 g (76%) of3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide. 1H-NMR(CDCl₃) d (ppm): 8.07 (s, 1H), 7.96 (d, 1H), 7.45 (m, 2H), 5.60 (dw,2H), 3.32 (t, 2H) and 2.87 (t, 2H). Step 2:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionamide (1.2 g, 4.77mmol) was mixed with pyridine (0.829 g, 10.5 mmol) and trifluoroaceticanhydride (1.2 g, 5.72 mmol) in dichloromethane (25 ml) at roomtemperature for 2 h. The reaction mixture was diluted withdichloromethane and washed with water and brine. The organic layer wasdried to give 1.1 g (98%) of3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile aspale-brown oil. 1H-NMR (CDCl₃) d (ppm): 8.09 (s, 1H), 7.98 (d, 1H), 7.45(m, 2H), 5.60 (dw, 2H), 3.35 (t, 2H) and 3.01 (t, 2H). Step 3:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid ethylester hydrochloride:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionitrile (1.1 g, 4.71mmol) was mixed with 24% HCl in ethanol (8 ml) overnight. Theprecipitate was filtered and washed with ether to give 0.99 g (66%) of3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid ethylester hydrochloride as white solid. 1H-NMR (DMSO-d6) d (ppm): 11.70 (w,2H), 7.78 (m, 2H), 7.64 (m, 2H), 4.41 (q, 2H), 3.45 (t, 2H), 3.22 (t,2H) and 1.28 (t, 3H).

Example 318 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acidhydrazide

Step 1: 3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid:3-Chloro-N-hydroxy-benzamidine 4.52 g, 26.5 mmol) was heated withsuccinic anhydride (2.65 mg, 26.5 mmol) in DMF (5 ml) at 150° C. for anh. The reaction mixture was cooled down and diluted with ethyl acetate.The organic solution was washed with water and brine, concentrated byvacuum. The residue was triturated with 20% ethyl acetate in hexanes togive 4.0 g (60%) of3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid as whitesolid.). 1H-NMR (CDCl₃) d (ppm): 8.08 (s, 1H), 7.96 (d, 1H), 7.49 (d,1H), 7.42 (t, 1H), 3.28 (t, 2H) and 3.04 (t, 2H). Step 2:3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide:This acid was reacted with iodoethane (1.6 g, 10.5 mmol) and K₂CO₃ (1.4610.5 mmol) in DMF (5 ml) for 5 min to form3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid ethylester. The ethyl ester was then treated with 37% hydrazine (2 ml) inethanol (5 ml) at 80° C. for 2 h to give 595 mg (65% in 3 steps) of3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazideas off-white solid 1H-NMR (CDCl₃) d (ppm): 8.07 (s, 1H), 7.96 (d, 1H),7.49 (d, 1H), 7.43 (t, 1H), 7.00 (w, 1H), 3.95 (w, 2H), 3.34 (t, 2H) and2.79 (t, 2H).

Example 319 [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acidhydrazide

Step 1: (N-Hydroxycarbamimidoyl)-acetic acid ethyl ester: To a ethanolsolution (40 ml) of cyano-acetic acid ethyl ester (9.9 g, 0.1 mol), themixture solution of sodium hydroxide (4 g, 0.1 mol) in water (40 ml) and5 M hydroxylamine hydrochloride (20 ml) was added and the reactionmixture was stirred at 50° C. overnight. After being concentrated, thereaction mixture was diluted with water and extrated with ethyl acetate.The organic layer was dried, concentrated again. The residue waspurified by column chromatography with 30˜70% ethyl acetate in hexanesto give 3.32 g (22.7%) of (N-Hydroxycarbamimidoyl)-acetic acid ethylester as white solid. 1H-NMR (CDCl₃) d (ppm): 5.04 (ws, 2H), 4.20 (q,2H), 3.19 (s, 2H) and 1.30 (t, 3H). Step 2:[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester: Toa dichloromethane solution (10 ml) of (N-hydroxycarbamimidoyl)-aceticacid ethyl ester (1.46 g, 10 mmol) and triethylamine, 3-chlorobenzoylchloride (1.75 g, 10 mmol) was added slowly at 5° C. and the reactionmixture was stirred for 10 min. DMF (8 ml) was added to the reactionmixture was heated to 135° C. for 2 h. Standard work-up, the product waspassed column with dichloromethane to give 1.2 g (45%) of[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethyl ester aspale-yellow oil. 1H-NMR (CDCl₃) d (ppm): 8.168 (s, 1H), 8.04 (d, 1H),7.59 (d, 1H), 7.49 (t, 1H), 4.26 (q, 2H), 3.91 (s, 2H) and 1.31 (t, 3H).Step 3: [5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acidhydrazide: 5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid ethylester (0.64 g, 2.4 mmol) was mixed with 37% hydrazine (1.6 ml) inethanol (10 ml) at 80° C. for 4 h. The reaction mixture was concentratedand diluted with water. The precipitate was filtered, washed with waterto give 0.51 g (83.3%) of[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-acetic acid hydrazide.

Example 320 (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyricacid hydrazide

Step 1: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acidmethyl ester: To a solution of (R)-2-methylsuccinic acid 4-methyl ester(2.2 g, 15 mmol) and triethylamine (4.54 g, 45 mmol) in THF (30 ml),isobutylchloroformate (2.16 g, 15.8 mmol) was added dropwise at 0° C.After being stirred for 30 min, the 3-chloro-N-hydroxy-benzamidine (2.56g, 15 mmol) was added. The reaction mixture was stirred at roomtemperature for another 30 min and then heated to 135° C. with DMF for45 min. The reaction mixture was diluted with ethyl acetate and washedwith water and brine. The organic layer was dried and concentrated togive 4.0 g (95%) of(R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid methylester as pale-yellow oil. Step 2:(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acidhydrazide: (R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyricacid hydrazide (430 mg, 77%) was obtained from(R)-3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid methylester (461.4 mg, 2.0 mmol) reacted with hydrazine hydrate (2 mL) inmethanol (2 mL) at 65° C. for 1 h. 1H-NMR (CDCl₃) d (ppm): 8.07 (s, 1H),7.96 (d, 1H), 7.46 (m, 2H), 6.98 (w, 1H), 3.93 (w, 2H), 3.78 (m, 1H),2.86 (dd, 1H), 2.55 (dd, 1H) and 1.59 (d, 3H).

The following compounds were prepared analogously to Example 320:Example No. Name 321 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-3-methyl-butyric acid hydrazide

Example 3223-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one

1.33 ml (3.32 mmol) n-BuLi (2.5 M in hexanes) was added dropwise to asolution of 157 mg (1.58 mmol) d-valerolactone in 5,3 ml THF at 0° C.After stirring for 2 h at 0° C., 400 mg (1.58 mmol)3-chloromethyl-5-[3-chloro-phenyl)-[1,2,4]oxadiazole was added in oneportion and stirring was continued for 3 h. NH₄Cl(sat) was added toquench the reaction and the mixture was extracted twice with CH₂Cl₂. Thecombined organic phases were dried and concentrated. Flashchromatography(SiO₂, Heptane/EtOAc 1:8) afforded 113 mg (25%) of a yellow-white solid.1H NMR (CDCl₃): d ppm 1.80 (m, 1H) 1.89 (m, 1H) 2.00 (m, 1H) 2.91 (m,1H) 2.98 (m, 1H) 3.35 (m, 1H) 3.52 (m, 1H) 5.83 (s, 1H) 7.46 (t, 1H)7.55 (d, J=8.08 Hz, 1H) 8.00 (d, 1H) 8.11 (s, 1H).

The following compounds were prepared analogously to Example 322:Example No. Name 323 3-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one

Example 324 3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazoleand1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole

A solution of 2-chloro-N-hydroxy-acetamidine (781 mg, 7.2 mmol),5-chloro-thiophene-3-carboxylic acid (1.4 g), HBTU (3.55 g) and DIPEA(1.3 g) in DMF (20 ml) was stirred at ambient temperature for 1 h beforeheated at 120° C. for 4 h under argon. Removal of the solvent in vacuofollowed by silica gel chromatography of the obtained residue using0-20% EtOAc in n-heptane yielded 38.5 mg of the faster eluting3-chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole as a syrup,followed by 65 mg of the slower eluting1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazoleas a white solid.3-Chloromethyl-5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazole: 1H NMR(CDCl₃) d (ppm): 8.01 (d, 1H), 7.50 (d, 1H), 4.63 (s, 2H).1-[5-(5-Chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole:1H NMR (CDCl₃) d (ppm): 7.97 (m, 2H), 7.52 (dt, 1H), 7.44 (m, 2H), 7.34(m, 1H), 5.70 (s, 2H).

Example 325(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetonitrile

4-Methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (197 mg, 1.0 mmol),chloroacetonitile (95 ml, 1.5 mmol), sodium carbonate (424 mg, 4 mmol)and potassium iodide (332 mg, 2.0 mmol) were stirred together at 100° C.for 3 h with an additional addition of chloroacetonitrile (60 ml, 0.5mmol) after 2 h. The reaction was cooled, diluted with ethyl acetate andwashed with water. The organic solution was dried, filtered andevaporated. Silica gel chromatography (dichloromethane:methanol 19:1)yielded 150 mg of the desired compound.

Example 3262-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionicacid

(R)-2-chloro-propionic acid (500 mg, 4.6 mmol),4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (1.09 g, 5.58 mmol)and potassium carbonate (1.94 g, 14.03 mmol) were dissolved inacetonitrile (15 ml) at room temperature. Reaction proceeded for 2.5 hand was partitioned between ethyl acetate (350 ml) and water 3 times,washed with 1 M HCl, once with saturated brine, dried over anhydroussodium sulphate, filtered and concentrated in vacuo. Reaction was notcompleted at this stage and the crude was stirred in DMF (10 ml)overnight. Extraction was repeated and purification was performed by SPE(solid phase extraction) chromatography on silica gel using 300 ml ethylacetate, 100 ml 1%, and 100 ml 3% formic acid in ethyl acetate, yieldingtitle compound (150.7 mg, 12%) 1H-NMR (CDCl₃), d (ppm): 7.52 (dd, 2H),7.19 (m, 1H), 4.21 (q, 1H), 3.78 (s, 3H), 1.64 (d, 3H).

The following compounds were prepared analogously to Example 326:Example No. Name 327 2-(4-Methyl-5-pyridin-3-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionic acid

Example 3283-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

The title compound (2.08 g, 81.5%) was obtained form5-chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole (1.9 g, 8.29 mmol)reacted with 4-methyl-4H-[1,2,4]triazole-3-thiol (1.0 g, 8.71 mmol) andK₂CO₃ (4.58 g, 33.2 mmol) in DMF (19 ml) at room temperature overnight.1H-NMR (CDCl₃) d (ppm): 8.21 (s, 1H), 8.05 (s, 1H), 7.94 (d, 1H), 7.49(d, 1H), 7.43 (t, 1H), 4.69 (s, 2H) and 3.64 (s, 3H).

Example 329{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl-phenyl}-carbamicacid tert-butyl ester

The title compound was prepared from4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3-thiol (53 mg, 0.27 mmol),3-(3-chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-carbamic acidtert-butyl ester (75 mg, 0.24 mmol), and potassium carbonate (101 mg,0.73 mmol) in acetonitrile (2.5 ml). The product was purified by SPE(flash) chromatography using 65% ethyl acetate in hexane (88.0 mg, 79%,white solid). ¹H NMR (CDCl₃) d (ppm): 8.06 (s, 1H), 7.73 (d, 1H), 7.66(d, 1H), 7.51 (t, 2H), 7.42 (t, 1H), 7.18 (m, 1H), 6.68 (s, 1H), 4.51(s, 2H), 3.73 (s, 3H), 1.53 (s, 9H).

The following compounds were prepared analogously to Example 41: ExampleNo. Name 1H NMR MS 330 4-(4-Cyclopropyl-5-{1-[5-(2,5- 8.88 (d, 2H), 7.81(m, difluoro-phenyl)-[1,2,4]oxadiazol-3- 1H), 7.75 (m, 2H),yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.22 (m, 2H), 5.42 (q, 1H),3-yl)-pyridine 3.22 (m, 1H), 1.98 (d, 3H), 1.17 (m, 2H), 0.79 (m, 2H)331 4-(5-{1-[5-(3-Methoxy-phenyl)- 8.69 (m, 2H), 7.6 (m,[1,2,4]oxadiazol-3-yl]- 1H), 7.52 (m, 3H), ethylsulfanyl}-4-methyl-4H-7.35 (t, 1H), 7.04 (m, 1H), [1,2,4]triazol-3-yl)-pyridine 4.93 (q, 1H),3.78 (t, 3H), 3.55 (s, 3H), 1.86 (d, 3H) 3324-{4-Methyl-5-[1-(5-m-tolyl- 8.71 (m, 2H), 7.82 (m,[1,2,4]oxadiazol-3-yl)- 2H), 7.53 (m, 2H),ethylsulfanyl]-4H-[1,2,4]triazol-3- 7.32 (m, 2H), 4.94 (q, 1H),yl}-pyridine 3.54 (s, 3H), 2.33 (s, 3H), 1.87 (d, 3H) 3335-(4-Methyl-5-thiophen-2-yl-4H- 2.58 (s, 3H) 3.70 (s, 3H) 370.0[1,2,4]triazol-3-ylsulfanylmethyl)-3- 4.65 (s, 2H) 7.17 (s,o-tolyl-[1,2,4]oxadiazole 1H) 7.29 (s, 2H) 7.36 (s, 1H) 7.46 (s, 1H)7.51 (s, 1H) 7.90 (s, 1H) 334 5-(3-Chloro-phenyl)-3-(4- 0.87 (m, 2H)1.18 (m, 2H) 415.9 cyclopropyl-5-thiophen-2-yl-4H- 3.47 (ddd, J = 6.95,[1,2,4]triazol-3-ylsulfanylmethyl)- 3.41, 3.28 Hz, 1H) [1,2,4]oxadiazole4.70 (s, 2H) 7.23 (m, 1H) 7.67 (m, 2H) 7.77 (m, 2H) 8.04 (d, 2H) 3352-{3-[5-(2-Fluoro-5-methyl- 2.36 (s, 3H) 4.03 (t, 2H) 417.9phenyl)-[1,2,4]oxadiazol-3- 4.30 (t, 2H) 4.57 (s,ylmethylsulfanyl]-5-thiophen-2-yl- 2H) 7.11 (m, 2H)[1,2,4]triazol-4-yl}-ethanol 7.35 (s, 1H) 7.47 (d, 1H) 7.64 (d, 1H) 7.81(d, 1H) 336 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 1.38 (t, 3H) 2.34 (s,3H) 398.0 phenyl)-[1,2,4]oxadiazol-3- 4.66 (m, 4H)ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.19 (m, 1H) 7.47 (m, 1H)3-yl}-pyrimidine 7.83 (d, 1H) 8.23 (d, 1H) 8.94 (d, 1H) 9.28 (s, 1H) 3373-(4-Ethyl-5-furan-3-yl-4H- 1.34 (t, 3H) 2.37 (s, 3H) 386.0[1,2,4]triazol-3-ylsulfanylmethyl)-5- 4.06 (q, 2H) 4.61 (s,(2-fluoro-5-methyl-phenyl)- 2H) 6.82 (s, 1H) [1,2,4]oxadiazole 7.12 (m,1H) 7.36 (ddd, 1H) 7.55 (s, 1H) 7.85 (d, 2H). 338{3-[5-(2-Fluoro-5-methyl-phenyl)- 2.36 (s, 3H) 3.70 (s, 3H) 445.9[1,2,4]oxadiazol-3- 4.46 (s, 2H) 5.10 (s,ylmethylsulfanyl]-5-thiophen-2-yl- 2H) 7.21 (m, 2H)[1,2,4]triazol-4-yl}-acetic acid 7.47 (m, 2H) 7.73 (d, 1H) methyl ester7.86 (m, 1H) 339 5-(2-Fluoro-5-methyl-phenyl)-3-[5- 2.26 (s, 3H) 3.16(s, 3H) 416.0 furan-2-yl-4-(2-methoxy-ethyl)-4H- 3.57 (t, 2H) 4.42 (t,[1,2,4]triazol-3-ylsulfanylmethyl]- 2H) 4.44 (s, 2H) [1,2,4]oxadiazole6.60 (s, 1H) 7.10 (m, 2H) 7.37 (m, 1H) 7.70 (s, 1H) 7.73 (d, 1H) 3403-(4-Cyclopropyl-5-furan-2-yl-4H- 0.87 (m, 2H) 1.14 (m, 2H) 398.0[1,2,4]triazol-3-ylsulfanylmethyl)-5- 2.35 (s, 3H) 3.39 (dt,(2-fluoro-5-methyl-phenyl)- 1H) 4.71 (s, 2H) [1,2,4]oxadiazole 6.72 (s,1H) 7.09 (d, 1H) 7.39 (m, 1H) 7.56 (m, 1H) 7.87 (d, 1H) 7.93 (s, 1H) 3413-(5-Chloro-2-fluoro-phenyl)-5-(4- 0.32 (m, 2H) 0.56 (m, 2H) 448.1cyclopropylmethyl-5-thiophen-2-yl- 1.14 (d, 1H) 4.00 (d,4H-[1,2,4]triazol-3- 2H) 4.76 (s, 2H)ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (ddd, 2H) 7.43 (m, 1H) 7.50 (t,2H) 7.99 (dd, 1H) 342 4-{5-[3-(5-Chloro-2-fluoro-phenyl)- 1.40 (t, 3H)4.63 (q, 2H) 417.8 [1,2,4]oxadiazol-5- 4.72 (s, 2H) 7.20 (m,ylmethylsulfanyl]-4-ethyl-4H- 1H) 7.53 (m, 1H)[1,2,4]triazol-3-yl}-pyrimidine 8.06 (dd, 1H) 8.29 (d, 1H) 8.86 (d, 1H)9.26 (s, 1H). 343 3-(5-Cyclopentyl-4-ethyl-4H- 1.29 (t, 3H) 1.66 (m, 3H)370.2 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1.87 (m, 2H)m-tolyl-[1,2,4]oxadiazole 2.02 (m, 3H) 2.42 (s, 3H) 3.01 (s, 2H) 3.90(d, 2H) 4.52 (s, 2H) 7.39 (d, 2H) 7.90 (d, 2H) 3443-(3-Chloro-phenyl)-5-{4-ethyl-5- 1.18 (t, 3H) 2.95 (t, 2H) 456.1[2-(4-methoxy-phenyl)-ethyl]-4H- 3.09 (t, 2H) 3.72 (q,[1,2,4]triazol-3-ylsulfanylmethyl}- 2H) 3.76 (s, 3H) [1,2,4]oxadiazole4.66 (s, 2H) 6.81 (d, 2H) 7.09 (d, 2H) 7.40 (t, 1H) 7.47 (m, 1H) 7.92(d, 1H) 8.03 (s, 1H) 345 5-(3-Chloro-phenyl)-3-(4-ethyl-5-p- 1.23 (t,3H) 2.22 (s, 3H) 442.1 tolyloxymethyl-4H-[1,2,4]triazol-3- 4.02 (d, 2H)4.60 (s, ylsulfanylmethyl)-[1,2,4]oxadiazole 2H) 5.22 (s, 2H) 6.92 (d,2H) 7.09 (d, 2H) 7.65 (t, 1H) 7.79 (d, 1H) 8.04 (m, 2H) 3465-(3-Chloro-phenyl)-3-[4-(2- 3.14 (s, 3H) 3.57 (t, 2H) 433.9methoxy-ethyl)-5-thiophen-2-yl-4H- 4.30 (t, 2H) 4.58 (s,[1,2,4]triazol-3-ylsulfanylmethyl]- 2H) 7.23 (m, 1H) [1,2,4]oxadiazole7.64 (m, 2H) 7.78 (m, 2H) 8.03 (d, 2H) 3473-(5-Chloro-2-fluoro-phenyl)-5-(4- 7.98 (m, 1H), 7.43 (m, 384.9ethyl-5-methoxymethyl-4H- 1H), 7.16 (apparent t,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 4.73 (s, 2H), [1,2,4]oxadiazole4.62 (s, 2H), 4.01 (q, 2H), 3.33 (s, 3H), 1.34 (t, 3H). 3485-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.05 (m, 1H), 7.53 (m, 384.9ethyl-5-methoxymethyl-4H- 1H), 7.21 (apparent t,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H); 4.62 (s, 2H), [1,2,4]oxadiazole4.61 (s, 2H), 4.02 (q, 2H), 3.34 (s, 3H), 1.32 (t, 3H). 3495-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.07 (apparent s, 1H), 366.9methoxymethyl-4H-[1,2,4]triazol-3- 7.97 (m, 1H), 7.55 (m,ylsulfanylmethyl)-[1,2,4]oxadiazole 1H), 7.45 (apparent t, 1H), 4.62 (s,2H), 4.59 (s, 2H), 4.01 (q, 2H), 3.34 (s, 3H), 1.32 (t, 3H). 3503-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.02 (m, 1H), 7.92 (m, 366.9methoxymethyl-4H-[1,2,4]triazol-3- 1H), 7.46 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.39 (apparent t, 1H), 4.71 (s, 2H),4.62 (s, 2H), 4.01 (q, 2H), 3.34 (s, 3H), 1.34 (t, 3H). 3514-(5-{1-[3-(3-Chloro-phenyl)- 1.82 (d, 3H), 3.46 (s, 3H), 399.1isoxazol-5-yl]-ethylsulfanyl}-4- 4.93 (q, 1H),methyl-4H-[1,2,4]triazol-3-yl)- 6.33 (s, 1H), 7.23-7.31 (m, 2H),pyridine 7.44 (d, 2H), 7.49 (m, 1H), 7.61 (s, 1H), 8.63 (d, 2H). 3523-(4-Allyl-5-furan-2-yl-4H- 4.6 (s, 2H), 4.8 (d, 2H), 399.95[1,2,4]triazol-3-ylsulfanylmethyl)-5- 5.0 (d, 1H), 5.2 (d, 1H),(3-chloro-phenyl)-[1,2,4]oxadiazole 5.9 (m, 1H), 6.5 (m, 1H), 7.1 (d,1H), 7.4 (t, 1H), 7.5 (m, 2H), 8.0 (d, 1H), 8.1 (s, 1H) 3533-(4-Allyl-5-furan-2-yl-4H- 4.5 (s, 2H) 4.8 (d, 2H) 371.98[1,2,4]triazol-3-ylsulfanylmethyl)-5- 5.0 (d, 1H) 5.2 (d, 1H)thiophen-3-yl-[1,2,4]oxadiazole 5.9 (m, 1H) 6.5 (m, 1H) 7.0 (d, 1H) 7.4(m, 1H) 7.5 (s, 1H) 7.6 (d, 1H) 8.2 (m, 1H) 3545-(4-Allyl-5-furan-2-yl-4H- 4.7 (s, 2H) 4.8 (m, 2H) 356.01[1,2,4]triazol-3-ylsulfanylmethyl)-3- 5.0 (d, 1H) 5.2 (d, 1H)furan-2-yl-[1,2,4]oxadiazole 5.9 (m, 1H) 6.5 (dt, 2H) 7.1 (dd, 2H) 7.6(dd, 2H) 355 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 1.4 (t, 3H) 3.7 (s, 3H)457.91 (4-methoxy-phenoxymethyl)-4H- 4.1 (q, 2H) 4.6 (s, 2H)[1,2,4]triazol-3-ylsulfanylmethyl]- 5.2 (s, 2H) 6.8 (d, 2H)[1,2,4]oxadiazole 6.9 (d, 2H) 7.4 (t, 1H) 7.6 (d, 1H) 8.0 (d, 1H) 8.1(s, 1H) 356 3-(3-Chloro-phenyl)-5-[4-ethyl-5- 1.4 (t, 3H) 3.7 (s, 3H)457.97 (4-methoxy-phenoxymethyl)-4H- 4.1 (q, 2H) 4.8 (s, 2H)[1,2,4]triazol-3-ylsulfanylmethyl]- 5.2 (s, 2H) 6.8 (d, 2H)[1,2,4]oxadiazole 6.9 (d, 2H) 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (d, 1H) 8.0(s, 1H) 357 {5-[3-(3-Chloro-phenyl)- 1.4 (t, 3H) 4.2 (d, 2H) 352.09[1,2,4]oxadiazol-5- 4.7 (s, 2H) 4.9 (s, 2H)ylmethylsulfanyl]-4-ethyl-4H- 7.4 (t, 1H) 7.5 (m, 1H)[1,2,4]triazol-3-yl}-methanol 7.9 (d, 1H) 8.0 (s, 1H) 3583-(3-Chloro-phenyl)-5-[4-ethyl-5- 1.3 (t, 3H) 3.0 (t, 2H) 380.12(2-methoxy-ethyl)-4H- 3.3 (s, 3H) 3.8 (t, 2H)[1,2,4]triazol-3-ylsulfanylmethyl]- 3.9 (q, 2H) 4.7 (s, 2H)[1,2,4]oxadiazole 7.4 (t, 1H) 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t, 1H) 3593-(3-Chloro-phenyl)-5-(4-ethyl-5- 1.4 (t, 3H) 2.1 (s, 3H) 382.07methylsulfanylmethyl-4H- 3.8 (s, 2H) 4.0 (q, 2H)[1,2,4]triazol-3-ylsulfanylmethyl)- 4.7 (s, 2H) 7.4 (t, 1H)[1,2,4]oxadiazole 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t, 1H) 3603-(3-Chloro-phenyl)-5-(5- .2 (t, 3H) 1.3 (t, 3H) 379.13ethoxymethyl-4-ethyl-4H- 3.5 (q, 2H) 4.0 (q, 2H)[1,2,4]triazol-3-ylsulfanylmethyl)- 4.7 (s, 2H) 4.7 (s, 2H)[1,2,4]oxadiazole 7.4 (t, 1H) 7.5 (ddd, 1H) 7.9 (dt, 1H) 8.0 (t, 1H) 3615-[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethylsulfanyl]-4-ethyl-4H- [1,2,4]triazole-3-carboxylic acid methylester 362 2-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.4 (t 3H) 4.2 (q, 2H)406.07 ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.7 (s, 2H) 6.6 (dd, 1H)3-ylsulfanylmethyl)- 7.1 (d, 1H) 7.2 (m, 1H) [1,3,4]oxadiazole 7.5 (ddd,1H) 7.6 (d, 1H) 8.0 (dd, 1H) 363 2-(3-Chloro-phenyl)-5-(4- 0.9 (m, 2H)1.2 (m, 2H) 399.86 cyclopropyl-5-furan-2-yl-4H- 3.2 (m, 1H) 4.8 (s, 2H)[1,2,4]triazol-3-ylsulfanylmethyl)- 6.6 (m, 1H) 7.0 (d, 1H)[1,3,4]oxadiazole 7.4 (t, 1H) 7.5 (m, 1H) 7.6 (m, 1H) 7.9 (m, 1H) 8.0(m, 1H) 364 5-(3-Chloro-phenyl)-3-{1-[4-ethyl- 1.3 (t, 3H) 1.9 (d, 3H)406.04 5-(tetrahydro-furan-2-yl)-4H- 2.0 (m, 1H) 2.1 (m, 1H)[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 2.3 (m, 1H) 2.8 (m,[1,2,4]oxadiazole 1H) 3.8 (m, 2H) 4.0 (m, 1H) 4.1 (m, 1H) 5.0 (m, 1H)5.1 (m, 1H) 7.4 (t, 1H) 7.6 (m, 1H) 8.0 (m, 1H) 8.1 (s, 1H) 3654-(5-{1-[5-(3-Chloro-phenyl)- 1.4 (t, 3H) 1.9 (d, 3H) 414.12[1,2,4]oxadiazol-3-yl]- 4.1 (m, 2H) 5.2 (q, 1H)ethylsulfanyl}-4-ethyl-4H- 7.4 (t, 1H) 7.5 (m, 1H)[1,2,4]triazol-3-yl)-pyridazine 7.8 (m, 1H) 8.0 (m, 1H) 8.1 (m, 1H) 9.4(m, 1H) 9.5 (s, 1H) 366 4-(5-{1-[5-(3-Chloro-phenyl)- 1.0 (t, 3H) 1.9(d, 3H) 427.06 [1,2,4]oxadiazol-3-yl]- 3.7 (m, 2H) 4.2 (m, 2H)ethylsulfanyl}-4-ethyl-4H- 5.0 (q, 1H) 7.1 (m, 2H)[1,2,4]triazol-3-ylmethyl)-pyridine 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (d, 1H)8.1 (s, 1H) 8.5 (m, 2H) 367 5-(5-{1-[5-(3-Chloro-phenyl)- 1.3 (t, 3H)1.9 (d, 3H) 429.1 [1,2,4]oxadiazol-3-yl]- 3.9 (m, 2H) 5.1 (q, 1H)ethylsulfanyl}-4-ethyl-4H- 6.7 (d, 1H) 7.5 (t, 1H)[1,2,4]triazol-3-yl)-pyridin-2-ol 7.6 (m, 1H) 7.7 (m, 1H) 7.7 (s, 1H)8.0 (d, 1H) 8.1 (s, 1H) 13.1 (s, 1H) 368 4-(5-{1-[5-(3-Chloro-phenyl)-1.2 (t, 3H) 1.9 (d, 3H) 428.08 [1,2,4]oxadiazol-3-yl]- 3.9 (q, 2H) 5.1(q, 1H) ethylsulfanyl}-4-ethyl-4H- 6.9 (d, 2H) 7.3 (d, 2H)[1,2,4]triazol-3-yl)-phenol 7.4 (t, 1H) 7.5 (m, 1H) 7.9 (m, 1H) 8.1 (m,1H) 10.2 (s, 1H) 369 5-(3-Chloro-phenyl)-3-[5-(4- 1.54 (m, 1H) 1.86 (m,2H) methoxy-phenoxymethyl)-4- 2.02 (m, 1H)(tetrahydro-furan-2-ylmethyl)-4H- 3.71 (m, 4H) 3.79 (m, 1H)[1,2,4]triazol-3-ylsulfanylmethyl]- 4.13 (m, 3H) 4.60 (m, 2H)[1,2,4]oxadiazole 5.30 (s, 2H) 6.82 (m, 2H) 6.92 (m, 2H) 7.44 (t, 1H)7.55 (d, 1H) 7.95 (d, 1H) 8.07 (s, 1H) 370 5-(3-Chloro-phenyl)-3-[4-1.14 (m, 4H) 3.10 (s, 1H) cyclopropyl-5-(4-methoxy- 3.75 (s, 3H) 4.70(s, phenoxymethyl)-4H-[1,2,4]triazol- 2H) 5.21 (s, 2H)3-ylsulfanylmethyl]- 6.82 (d, 2H) 6.95 (d, 2H) [1,2,4]oxadiazole 7.45(t, 1H) 7.56 (m, 1H) 7.99 (d, 1H) 8.10 (s, 1H) 3715-(5-Chloro-2-fluoro-phenyl)-3-(4- 1.38 (t, 3H) 4.27 (q, 2H)ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.64 (s, 2H) 6.58 (m,3-ylsulfanylmethyl)- 1H) 7.21 (m, 2H) [1,2,4]oxadiazole 7.53 (m, 1H)7.59 (m, 1H) 8.06 (m, 1H) 372 3-(4-Ethyl-5-methoxymethyl-4H- 1.29 (t,3H) 2.40 (s, 3H) 346 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 3.31 (s, 3H)3.99 (m, m-tolyl-[1,2,4]oxadiazole 2H) 4.56 (s, 2H) 4.60 (s, 2H) 7.37(m, 2H) 7.87 (m, 2H) 373 3-[4-Ethyl-5-(tetrahydro-furan-2- 1.30 (t, 3H)1.97 (m, 1H) 372 yl)-4H-[1,2,4]triazol-3- 2.10 (m, 1H)ylsulfanylmethyl]-5-m-tolyl- 2.24 (m, 1H) 2.39 (s, 3H) [1,2,4]oxadiazole2.80 (m, 1H) 3.79 (m, 1H) 3.86 (m, 1H) 3.99 (m, 1H) 4.08 (m, 1H) 4.54(m, 2H) 4.98 (m, 1H) 7.36 (m, 2H) 7.86 (m, 1H) 7.88 (s, 1H) 3742-(3-Chloro-phenyl)-5-{1-[4-ethyl- 1.18 (m, 3H) 1.95 (d, 3H)5-(4-methoxy-phenyl)-4H- 3.81 (s, 3H) 3.90 (q,[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 2H) 5.15 (q, 1H) [1,3,4]oxadiazole6.94 (m, 2H) 7.35 (m, 1H) 7.45 (m, 3H) 7.81 (m, 1H) 7.92 (m, 1H) 3754-{5-[3-(2,5-Difluoro-phenyl)- 1.43 (t, 3H), 4.64 (q, 2H), 402.1[1,2,4]oxadiazol-5- 4.87 (s, 2H), ylmethylsulfanyl]-4-ethyl-4H- 7.18 (m,2H), 7.72 (m, 1H), [1,2,4]triazol-3-yl}-pyrimidine 8.29 (dd, 1H), 8.89(d, 1H), 9.30 (d, 1H) 376 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 4.12 (s,3H), 4.64 (s, 2H), 404.1 [1,2,4]oxadiazol-3- 7.21 (t, 1H),ylmethylsulfanyl]-4-methyl-4H- 7.57 (m, 1H), 8.06 (dd, 1H),[1,2,4]triazol-3-yl}-pyrimidine 8.28 (dd, 1H), 8.92 (d, 1H), 9.30 (d,1H) 377 3-(3-Chloro-phenyl)-5-(4-methyl-5- 8.03 (s, 1H), 7.92 (d, 390.96thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.53 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.48 (m, 2H), 7.40 (t, 1H), 7.18 (t,1H), 4.87 (s, 2H), 3.72 (s, 3H). 378 5-(3-Methylsulfanyl-phenyl)-3-(4-7.92 (s, 1H), 7.84 (d, methyl-5-thiophen-2-yl-4H- 1H), 7.53 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.43 (m, 2H), 7.18 (m, 1H),[1,2,4]oxadiazole 4.53 (s, 2H), 3.73 (s, 3H), 2.52 (s, 3H). 3792-[5-(3-Methylsulfanyl-phenyl)- [1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H- benzoimidazole 380 5-(2,5-Dimethyl-phenyl)-3-(4-7.87 (s, 1H), 7.49 (m, methyl-5-thiophen-2-yl-4H- 2H), 7.22 (m, 3H),[1,2,4]triazol-3-ylsulfanylmethyl)- 4.56 (d, 2H), 3.74 (s, 3H),[1,2,4]oxadiazole 2.61 (s, 3H), 2.37 (s, 3H). 3815-(2-Fluoro-5-methyl-phenyl)-3-(4- 7.83 (dd, 1H), 7.49 (m, 388.10methyl-5-thiophen-2-yl-4H- 2H), 7.35 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.16 (m, 2H), 4.53 (s, 2H),[1,2,4]oxadiazole 3.73 (s, 3H), 2.35 (s, 3H). 3825-(3-Cyclopropyl-phenyl)-3-(4- 7.87 (d, 1H), 7.79 (s,methyl-5-thiophen-2-yl-4H- 1H), 7.51 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.40 (t, 1H), 7.30 (m, 1H),[1,2,4]oxadiazole 7.20 (m, 1H), 4.53 (s, 2H), 3.73 (s, 3H), 1.96 (m,1H), 1.04 (m, 2H), 0.77 (m, 2H). 383 4-{5-[2-(3-Chloro-phenyl)-oxazol-8.80 (d, 2H), 8.02 (dd, 4-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.88 (dd,1H), [1,2,4]triazol-3-yl}-pyridine 7.80 (s, 1H), 7.60 (d, 2H), 7.42 (m,2H), 4.51 (s, 2H), 3.64 (s, 3H). 384 4-[4-Methyl-5-(5-thiophen-2-yl-8.82 (bs, 2H), 7.90 (m, [1,2,4]oxadiazol-3- 1H), 7.66 (m, 3H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.22 (m, 1H), 4.58 (s, 2H),3-yl]-pyridine 3.73 (s, 3H). 385 4-{4-Methyl-5-[5-(3- 8.81 (m, 2H), 7.95(s, methylsulfanyl-phenyl)- 1H), 7.86 (m, 1H), [1,2,4]oxadiazol-3- 7.64(m, 2H), 7.45 (m, 2H), ylmethylsulfanyl]-4H-[1,2,4]triazol- 4.63 (s,2H), 3.72 (s, 3-yl}-pyridine 3H), 2.55 (3H). 3864-{5-[5-(3-Chloro-phenyl)- 8.83 (d, 2H), 8.11 (s, [1,2,4]oxadiazol-3-1H), 8.00 (d, 1H), ylmethylsulfanyl]-4-methyl-4H- 7.64 (m, 2H), 7.60 (m,1H), [1,2,4]triazol-3-yl}-pyridine 7.49 (t, 1H), 4.64 (s, 2H), 3.73 (s,3H). 387 2-Methyl-4-[3-(4-methyl-5-pyridin- 8.82 (d, 2H), 8.74 (d,4-yl-4H-[1,2,4]triazol-3- 1H), 7.82 (s, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.76 (d, 1H), 7.64 (d, 2H),5-yl]-pyridine 4.68 (s, 2H), 3.74 (s, 3H), 2.68 (s, 3H). 3881-{3-[3-(4-Methyl-5-thiophen-2-yl- 8.67 (s, 1H), 8.29 (d,4H-[1,2,4]triazol-3- 1H) 8.20 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.68 (t, 1H), 7.52 (m, 2H),5-yl]-phenyl}-ethanone 7.20 (m, 1H), 4.58 (s, 2H), 3.76 (s, 3H), 2.68(s, 3H). 389 4-{5-[5-(2-Fluoro-5-methyl- 8.81 (dd, 2H), 7.86 (d, 383.09phenyl)-[1,2,4]oxadiazol-3- 1H), 7.64 (m, 2H),ylmethylsulfanyl]-4-methyl-4H- 7.39 (m, 1H), 7.14 (dd, 1H),[1,2,4]triazol-3-yl}-pyridine 4.63 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H).390 2-Methyl-4-[4-methyl-5-(5-m-tolyl- 8.68 (dd, 1H), 7.92 (m,[1,2,4]oxadiazol-3- 2H), 7.52 (bs, 1H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.4 (m, 3H), 4.61 (s, 2H),3-yl]-pyridine 3.7 (s, 3H), 2.67 (s, 3H), 2.44 (s, 3913H). 3913-[5-(3-Chloro-phenyl)-isoxazol-3- 7.76 (s, 1H), 7.68 (m,ylmethylsulfanyl]-4-methyl-5- 1H), 7.54 (m, 1H),thiophen-2-yl-4H-[1,2,4]triazole 7.48 (m, 1H), 7.40 (m, 2H), 7.20 (m,1H), 6.76 (s, 1H), 4.56 (s, 2H), 3.70 (s, 3H). 3924-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.82 (m, 2H), 7.76 (m,3-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.65 (m, 3H),[1,2,4]triazol-3-yl}-pyridine 7.41 (m, 2H), 6.77 (s, 1H), 4.61 (s, 2H),3.69 (s, 3H). 393 3-(4-Butyl-5-thiophen-2-yl-4H- 8.07 (s, 1H), 7.95 (dd,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.48 (m, 4H),(3-chloro-phenyl)-[1,2,4]oxadiazole 7.17 (dd, 1H), 4.59 (s, 2H), 4.05(t, 2H), 1.67 (m, 2H), 1.30 (m, 2H), 0.88 (t, 3H). 3945-(3-Chloro-phenyl)-3-[4-(3- 8.01 (d, 1H), 7.91 (dd,methoxy-propyl)-5-thiophen-2-yl- 1H), 7.48 (m, 4H), 4H-[1,2,4]triazol-3-7.12 (m, 1H), 4.51 (s, 2H), ylsulfanylmethyl]-[1,2,4]oxadiazole 4.17 (t,2H), 3.34 (t, 2H), 3.18 (s, 3H), 1.90 (m, 2H). 3953-(4-Benzyl-5-thiophen-2-yl-4H- 8.09 (s, 1H), 7.97 (dd,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.57 (m, 1H),(3-chloro-phenyl)-[1,2,4]oxadiazole 7.47 (m, 2H), 7.24 (m, 4H), 7.06 (m,3H), 5.37 (s, 2H), 4.57 (s, 2H). 396 5-(3-Chloro-phenyl)-3-(4-furan-2-8.10 (d, 1H), 8.03 (dd, 457.02 ylmethyl-5-thiophen-2-yl-4H- 1H), 7.55(m, 4H), [1,2,4]triazol-3-ylsulfanylmethyl)- 7.38 (s, 1H), 7.20 (dd,1H), [1,2,4]oxadiazole 6.32 (m, 2H), 5.30 (s, 2H), 4.60 (s, 2H). 3973-{5-[5-(3-Chloro-phenyl)- 8.93 (m, 1H), 8.78 (m, [1,2,4]oxadiazol-3-1H), 8.03 (m, 3H), ylmethylsulfanyl]-4-methyl-4H- 7.59 (m, 1H), 7.51 (m,2H), [1,2,4]triazol-3-yl}-pyridine 4.63 (s, 2H), 3.69 (s, 3H). 3985-(3-Chloro-phenyl)-3-(4-methyl-5- 8.11 (m, 1H), 8.05 (m,thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.74 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.59 (m, 1H), 7.51 (m, 3H), 4.57 (s,2H), 3.71 (s, 3H). 399 4-{5-[5-(3-Chloro-phenyl)- 8.69 (d, 1H), 8.10 (s,[1,2,4]oxadiazol-3- 1H), 8.00 (m, 1H), ylmethylsulfanyl]-4-methyl-4H-7.49 (m, 4H), 4.63 (s, 2H), [1,2,4]triazol-3-yl}-2-methyl- 3.71 (s, 3H),2.67 (s, pyridine 3H). 400 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m,1H), 7.51 (m, 409.00 methyl-5-thiophen-2-yl-4H- 1H) 7.21 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 4.59 (s, 2H), 3.77 (s, 3H).[1,2,4]oxadiazole 401 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (d, 2H),8.08 (m, 404.07 [1,2,4]oxadiazol-3- 1H) 8.29 (d, 1H),ylmethylsulfanyl]-4-methyl-4H- 7.64 (d, 2H), 7.56 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.24 (t, 1H), 4.66 (s, 2H), 3.75 (s, 3H).402 3-{5-[5-(2-Fluoro-5-methyl- 8.92 (s, 1H), 8.76 (d,phenyl)-[1,2,4]oxadiazol-3- 1H), 8.07 (d, 1H),ylmethylsulfanyl]-4-methyl-4H- 7.87 (d, 1H), 7.36 (m, 3H),[1,2,4]triazol-3-yl}-pyridine 4.59 (s, 2H), 3.69 (s, 3H), 2.39 (s, 3H).403 5-(3-Chloro-phenyl)-3-(5-thiophen- (CD3OD as solvent):2-yl-4-thiophen-2-ylmethyl-4H- 8.05 (m, 1H), 8.00 (dd,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (dd, 1H),[1,2,4]oxadiazole 7.58 (m, 1H), 7.54 (m, 1H), 7.53 (m, 1H), 7.26 (m,1H), 7.22 (m, 1H), 6.86 (m, 2H), 5.63 (s, 2H), 4.51 (s, 2H). 4045-(3-Chloro-phenyl)-3-(4-ethyl-5- (CD3OD as 405.10thiophen-2-yl-4H-[1,2,4]triazol-3- solvent): 8.08 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 8.07 (dd, 1H), 7.75 (m, 1H), 7.67(m, 1H), 7.60 (m, 2H), 7.28 (dd, 1H), 4.57 (s, 2H), 4.27 (m, 2H), 1.29(m, 3H). 405 3-{5-[3-(2-Fluoro-5-methyl- 8.90 (m, 1H), 8.77 (dd,phenyl)-[1,2,4]oxadiazol-5- 1H), 8.03 (m, 1H),ylmethylsulfanyl]-4-methyl-4H- 7.78 (m, 1H), 7.48 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.28 (m, 1H), 7.12 (m, 1H), 4.73 (s, 2H),3.68 (s, 3H), 2.36 (s, 3H). 406 4-{5-[3-(2-Fluoro-5-methyl- 8.81 (m,2H), 7.77 (m, phenyl)-[1,2,4]oxadiazol-5- 1H), 7.62 (m, 2H),ylmethylsulfanyl]-4-methyl-4H- 7.31 (m, 1H), 7.11 (dd, 1H),[1,2,4]triazol-3-yl}-pyridine 4.75 (s, 2H), 3.72 (s, 3H), 2.37 (s, 3H).407 4-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.82 (m, 2H), 8.23 (m, 448.02[1,2,4]oxadiazol-3- 1H), 7.71 (m, 2H), ylmethylsulfanyl]-4-methyl-4H-7.65 (m, 1H), 7.18 (d, 1H), [1,2,4]triazol-3-yl}-pyridine 4.66 (s, 2H),3.75 (s, 3H). 408 3-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.92 (m, 1H), 8.76(m, [1,2,4]oxadiazol-3- 1H), 8.22 (m, 1H),ylmethylsulfanyl]-4-methyl-4H- 8.05 (m, 1H), 7.50 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.48 (m, 1H), 7.17 (dd, 1H), 4.63 (s, 2H),3.70 (s, 3H). 409 5-(5-Bromo-2-fluoro-phenyl)-3-(4- 8.23 (dd, 1H), 7.70(m, 452.90 methyl-5-thiophen-2-yl-4H- 1H), 7.52 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.19 (m, 2H), 4.49 (s, 2H),[1,2,4]oxadiazole 3.77 (s, 3H). 410 5-(4-Methyl-5-thiophen-3-yl-4H- 8.06(d, 2H) 7.34 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.51 (m,5H), phenyl-[1,2,4]oxadiazole 4.68 (s, 2H), 3.68 (s, 3H). 4113-{5-[5-(3-Fluoro-phenyl)- 8.92 (s, 1H), 8.78 (d, [1,2,4]oxadiazol-3-1H) 8.05 (d, 1H), ylmethylsulfanyl]-4-methyl-4H- 7.93 (d, 1H), 7.91 (d,1H), [1,2,4]triazol-3-yl}-pyridine 7.50 (m, 2H), 7.28 (t, 1H), 4.64 (s,2H), 3.70 (s, 3H). 412 4-{5-[5-(3-Fluoro-phenyl)- 8.82 (d, 2H), 7.93 (d,[1,2,4]oxadiazol-3- 1H) 7.90 (d, 1H), ylmethylsulfanyl]-4-methyl-4H-7.64 (d, 2H), 7.52 (m, 1H), [1,2,4]triazol-3-yl}-pyridine 7.33 (m, 1H),4.64 (s, 2H), 3.73 (s, 3H). 413 5-(3-Fluoro-phenyl)-3-(4-methyl-5- 7.90(d, 1H) 7.82 (d, thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.74 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.51 (m, 3H), 4.58 (s, 2H), 3.71 (s,3H). 414 3-[4-Methyl-5-(5-thiophen-3-yl- 8.91 (s, 1H), 8.78 (d,[1,2,4]oxadiazol-3- 1H) 8.23 (d, 1H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 8.04 (d, 1H), 7.66 (d, 1H),3-yl]-pyridine 7.49 (m, 2H), 4.60 (s, 2H), 3.69 (s, 3H). 4153-(4-Methyl-5-thiophen-3-yl-4H- 8.22 (d, 1H) 7.74 (d,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.63 (d, 1H),thiophen-3-yl-[1,2,4]oxadiazole 7.49 (m, 3H), 4.54 (s, 2H), 3.70 (s,3H). 416 2-Chloro-4-[3-(4-methyl-5-pyridin- 8.92 (s, 1H), 8.78 (d,3-yl-4H-[1,2,4]triazol-3- 1H) 8.65 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 8.04 (t, 2H), 7.89 (d, 1H),5-yl]-pyridine 7.51 (m, 1H), 4.69 (s, 2H), 3.71 (s, 3H). 4172-Chloro-4-[3-(4-methyl-5-pyridin- 8.82 (d, 2H), 8.65 (d,4-yl-4H-[1,2,4]triazol-3- 1H) 8.02 (s, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.89 (d, 1H), 7.64 (d, 2H),5-yl]-pyridine 4.70 (s, 2H), 3.74 (s, 3H). 4182-Chloro-4-[3-(4-methyl-5- 8.64 (d, 1H) 8.01 (s,thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.88 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.75 (d, 1H), 7.52 (m, 2H),5-yl]-pyridine 4.62 (s, 2H), 3.72 (s, 3H). 419 4-[4-Methyl-5-(5-phenyl-8.82 (d, 2H), 8.12 (d, [1,2,4]oxadiazol-3- 2H) 7.63 (m, 3H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.55 (m, 2H), 4.63 (s, 2H),3-yl]-pyridine 3.72 (s, 3H). 420 3-(4-Methyl-5-thiophen-3-yl-4H- 8.11(d, 2H) 7.74 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.57 (m,1H), phenyl-[1,2,4]oxadiazole 7.52 (m, 4H), 4.56 (s, 2H), 3.70 (s, 3H).421 5-(5-Bromo-2-fluoro-phenyl)-3-(4- (CD3OD asmethyl-5-thiophen-3-yl-4H- solvent): 8.21 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 8.02 (m, 1H), 7.82 (m,[1,2,4]oxadiazole 1H), 7.68 (m, 1H), 7.56 (m, 1H), 7.33 (t, 1H), 4.50(s, 2H), 3.82 (s, 3H). 422 3-[5-(3-Chloro-phenyl)-isoxazol-3- (CD3OD assolvent): 404.05 ylmethylsulfanyl]-4-ethyl-5- 7.84 (s, 1H), 7.75 (m,thiophen-2-yl-4H-[1,2,4]triazole 2H), 7.60 (m, 1H) 7.50 (m, 2H), 7.27(m, 1H), 6.92 (s, 1H), 4.51 (s, 2H), 4.23 (q, 2H), 1.33 (t, 3H). 4232-Chloro-4-[3-(4-methyl-5- 8.64 (d, 1H), 8.01 (s, 392.00thiophen-2-yl-4H-[1,2,4]triazol-3- 1H) 7.98 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.54 (d, 1H), 7.50 (d, 1H),5-yl]-pyridine 7.20 (m, 1H), 4.61 (s, 2H), 3.76 (s, 3H). 4244-{5-[3-(3-Fluoro-phenyl)- 8.83 (d, 2H), 7.85 (d, [1,2,4]oxadiazol-5-1H) 7.78 (d, 1H), ylmethylsulfanyl]-4-methyl-4H- 7.62 (d, 2H), 7.46 (m,1H), [1,2,4]triazol-3-yl}-pyridine 7.22 (m, 1H), 4.76 (s, 2H), 3.72 (s,3H). 425 3-(3-Fluoro-phenyl)-5-(4-methyl-5- 7.84 (d, 1H) 7.74 (m,thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.51 (m, 3H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.24 (m, 1H), 4.70 (s, 2H), 3.70 (s,3H). 426 3-(4-Ethyl-5-thiophen-2-yl-4H- (CD3OD as 384.13[1,2,4]triazol-3-ylsulfanylmethyl)-5- solvent): 7.89 (m, 2H),m-tolyl-[1,2,4]oxadiazole 7.76 (m, 1H), 7.60 (m, 1H), 7.47 (m, 2H), 7.27(m, 1H), 4.55 (s, 2H), 4.25 (q, 2H), 2.41 (s, 3H), 1.32 (s, 3H) 4273-(4-Ethyl-5-thiophen-2-yl-4H- (CD3OD as 402.09[1,2,4]triazol-3-ylsulfanylmethyl)-5- solvent): 7.85 (m, 1H),(2-fluoro-5-methyl-phenyl)- 7.75 (m, 1H), 7.60 (m, [1,2,4]oxadiazole1H), 7.55 (m, 1H), 7.27 (m, 1H), 7.22 (m, 1H), 4.57 (s, 2H), 4.27 (q,2H), 2.36 (s, 3H), 1.33 (s, 3H). 428 4-{5-[5-(3-Chloro-phenyl)- (CD3ODas 452.10 [1,2,4]oxadiazol-3- solvent): 8.75 (m, 2H),ylmethylsulfanyl]-4-furan-2- 8.04 (m, 2H), 7.78 (m,ylmethyl-4H-[1,2,4]triazol-3-yl}- 2H), 7.66 (m, 1H), pyridine 7.60 (m,1H), 7.37 (m, 1H), 6.30 (m, 2H), 5.42 (s, 2H), 4.56 (s, 2H). 4294-{5-[5-(3-Chloro-phenyl)- 8.80 (m, 2H), 8.09 (m, [1,2,4]oxadiazol-3-1H), 7.98 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H- 7.58 (m, 3H), 7.50 (dd,1H), [1,2,4]triazol-3-yl}-pyridine 4.69 (s, 2H), 4.12 (m, 2H), 1.36 (m,3H). 430 3-{5-[5-(3-Chloro-phenyl)- (CD3OD as 400.12 [1,2,4]oxadiazol-3-solvent): 8.87 (s, 1H), ylmethylsulfanyl]-4-ethyl-4H- 8.77 (d, 1H), 8.07(m, [1,2,4]triazol-3-yl}-pyridine 3H), 7.67 (m, 2H), 7.61 (dd, 1H), 4.62(s, 2H), 4.13 (m, 2H), 1.26 (m, 3H). 4315-(3-Chloro-phenyl)-3-(4-ethyl-5- (CD3OD as 405.07thiophen-3-yl-4H-[1,2,4]triazol-3- solvent): 7.79 (m, 3H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.67 (m, 2H), 7.51 (m, 2H), 4.56 (s,2H), 4.22 (q, 2H), 1.30 (t, 3H). 432 3-{5-[5-(3-Chloro-phenyl)- (CD3ODas 452.12 [1,2,4]oxadiazol-3- solvent): 8.86 (s, 1H),ylmethylsulfanyl]-4-furan-2- 8.76 (d, 1H), 8.07 (m,ylmethyl-4H-[1,2,4]triazol-3-yl}- 1H), 8.01 (m, 2H), pyridine 7.64 (m,3H), 7.36 (s, 1H), 6.29 (s, 2H), 5.37 (s, 2H), 4.55 (s, 2H). 4333-(4-Furan-2-ylmethyl-5-thiophen- (CD3OD as 436.162-yl-4H-[1,2,4]triazol-3- solvent): 7.87 (m, 2H),ylsulfanylmethyl)-5-m-tolyl- 7.73 (m, 1H), 7.63 (m, [1,2,4]oxadiazole1H), 7.45 (m, 3H), 7.25 (m, 1H), 6.31 (m, 2H), 5.42 (s, 2H), 4.49 (s,2H), 2.40 (s, 3H). 434 5-(5-Fluoro-2-methyl-phenyl)-3-(4- (CD3OD as454.12 furan-2-ylmethyl-5-thiophen-2-yl- solvent): 7.75 (dd, 1H),4H-[1,2,4]triazol-3- 7.69 (m, 1H), 7.66 (m,ylsulfanylmethyl)-[1,2,4]oxadiazole 1H), 7.41 (m, 1H), 7.38 (m, 1H),7.25 (m, 2H), 6.32 (s, 2H), 5.44 (s, 2H), 4.51 (s, 2H), 2.36 (s, 3H).435 5-(3-Chloro-phenyl)-3-(4-furan-2- 8.23 (s, 1H), 8.09 (m, 375.09ylmethyl-4H-[1,2,4]triazol-3- 1H), 7.97 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.48 (m, 1H), 7.45 (m, 1H), 7.37 (s,1H), 6.39 (m, 1H), 6.34 (m, 1H), 5.12 (s, 2H), 4.55 (s, 2H). 4363-[3-(4-Methyl-5-pyridin-3-yl-4H- 8.92 (s, 1H), 8.78 (d, 376.20[1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 8.43 (s, 1H),[1,2,4]oxadiazol-5-yl]-benzonitrile 8.35 (d, 1H), 8.05 (d, 1H), 7.91 (d,1H), 7.72 (t, 1H), 7.52 (m, 1H), 4.67 (s, 2H), 3.71 (s, 3H). 4373-[3-(4-Methyl-5-pyridin-4-yl-4H- 8.82 (d, 2H), 8.43 (s, 376.10[1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 8.35 (d, 1H),[1,2,4]oxadiazol-5-yl]-benzonitrile 7.90 (t, 1H), 7.64 (d, 2H), 4.68 (s,2H), 3.74 (s, 3H). 438 3-[3-(4-Methyl-5-thiophen-3-yl-4H- 8.42 (s, 1H),8.35 (d, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 7.89 (d, 1H),[1,2,4]oxadiazol-5-yl]-benzonitrile 7.72 (m, 2H), 7.52 (s, 1H), 4.61 (s,2H), 3.73 (s, 3H). 439 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m, 1H),7.54 (m, 423.12 ethyl-5-thiophen-2-yl-4H- 2H), 7.48 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.20 (m, 2H), 4.69 (s, 2H),[1,2,4]oxadiazole 4.18 (m, 2H), 1.39 (t, 3H). 4402-Chloro-4-[3-(4-ethyl-5-thiophen- 8.64 (d, 1H), 8.02 (s, 406.002-yl-4H-[1,2,4]triazol-3- 1H), 7.89 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.53 (d, 1H), 7.48 (d, 1H),5-yl]-pyridine 7.20 (t, 1H), 4.69 (s, 2H), 4.17 (m, 2H), 1.40 (t, 3H).441 3-(4-Ethyl-5-thiophen-2-yl-4H- 8.23 (s, 1H), 7.66 (d, 376.10[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.53 (d, 1H),thiophen-3-yl-[1,2,4]oxadiazole 7.48 (m, 2H), 7.19 (t, 1H), 4.63 (s,2H), 4.17 (m, 2H), 1.40 (t, 3H). 442 3-(4-Ethyl-5-thiophen-3-yl-4H- 7.93(m, 2H), 7.71 (m, 384.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.49(m, 2H), m-tolyl-[1,2,4]oxadiazole 7.42 (m, 2H), 4.63 (s, 2H), 4.10 (q,2H), 2.43 (s, 3H), 1.36 (t, 3H). 443 4-[4-Ethyl-5-(5-m-tolyl- 8.80 (m,2H), 7.91 (m, 379.20 [1,2,4]oxadiazol-3- 2H), 7.60 (m, 2H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.41 (m, 2H), 4.68 (s, 2H),3-yl]-pyridine 4.09 (m, 2H), 2.43 (s, 3H), 1.29 (s, 3H). 4443-[4-Ethyl-5-(5-m-tolyl- (CD3OD as 379.20 [1,2,4]oxadiazol-3- solvent):8.87 (s, 1H), ylmethylsulfanyl)-4H-[1,2,4]triazol- 8.77 (d, 1H), 8.02(m, 3-yl]-pyridine 1H), 7.92 (m, 2H), 7.49 (m, 1H), 7.42 (m, 2H), 4.67(s, 2H), 4.05 (q, 2H), 2.43 (s, 3H), 1.35 (t, 3H). 4453-(4-Ethyl-5-thiophen-3-yl-4H- 7.88 (dd, 1H), 7.71 (m,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.49 (m, 2H),(2-fluoro-5-methyl-phenyl)- 7.28 (m, 1H), 7.14 (dd, 1H),[1,2,4]oxadiazole 4.66 (s, 2H), 4.11 (q, 2H), 2.39 (s, 3H), 1.34 (t,3H). 446 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.80 (m, 2H), 7.86 (m,398.20 phenyl)-[1,2,4]oxadiazol-3- 1H), 7.60 (m, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.38 (m, 1H), 7.14 (dd, 1H),3-yl}-pyridine 4.70 (s, 2H), 4.11 (q, 2H), 2.39 (s, 3H), 1.36 (t, 3H).447 3-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.87 (s, 1H), 8.76 (d,phenyl)-[1,2,4]oxadiazol-3- 1H), 8.01 (m, 1H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.88 (m, 1H), 7.49 (m, 1H),3-yl}-pyridine 7.28 (m, 1H), 7.14 (dd, 1H), 4.69 (s, 2H), 4.07 (q, 2H),2.39 (q, 2H), 1.35 (t, 3H). 448 3-[5-(3-Chloro-phenyl)- (DMSO-D6 assolvent): 387.05 [1,2,4]oxadiazol-3- 8.75 (dd, 2H), 8.05 (m,ylmethylsulfanyl]-5-pyridin-4-yl- 4H), 7.79 (m, 1H),[1,2,4]triazol-4-ylamine 7.66 (dd, 1H), 6.33 (s, 2H), 4.65 (s, 2H). 4494-{5-[5-(5-Bromo-2-fluoro-phenyl)- 8.81 (dd, 2H), 8.24 (m, 464.02[1,2,4]oxadiazol-3- 1H), 7.71 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.61 (m, 2H), 7.18 (dd, 1H), [1,2,4]triazol-3-yl}-pyridine 4.72 (s, 2H),4.13 (m, 2H), 1.29 (m, 3H). 450 5-(4-Methyl-5-thiophen-3-yl-4H- 7.75 (m,2H), 7.51 (m, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 3H), 7.16 (m, 1H),thiophen-2-yl-[1,2,4]oxadiazole 4.64 (s, 2H), 3.70 (s, 3H). 4513-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.42 (s, 1H), 8.35 (d, 395.10[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.89 (d, 1H),[1,2,4]oxadiazol-5-yl]-benzonitrile 7.71 (t, 1H), 7.54 (d, 1H), 7.48 (d,1H), 7.20 (t, 1H), 4.68 (s, 2H), 4.16 (m, 2H), 1.40 (t, 3H). 4523-(4-Ethyl-5-thiophen-2-yl-4H- 8.13 (d, 2H), 7.49 (br 370.09[1,2,4]triazol-3-ylsulfanylmethyl)-5- m, 5H), 7.20 (m, 1H),phenyl-[1,2,4]oxadiazole 4.65 (s, 2H), 4.16 (m, 2H), 1.40 (t, 3H). 4534-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.36 (d, 1H), 7.51 (br[1,2,4]triazol-3-ylsulfanylmethyl)- m, 3H), 7.42 (s, 1H),[1,2,4]oxadiazol-5-yl]-2-methoxy- 7.19 (m, 1H), 4.68 (s, pyridine 2H),4.16 (m, 2H), 1.42 (t, 3H). 454 3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.06(s, 1H), 7.95 (d, thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.54 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.49 (m, 1H), 7.42 (m, 2H), 7.20 (m,1H), 4.78 (s, 2H), 4.17 (q, 2H), 1.41 (t, 3H). 4554-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.82 (m, 2H), 7.76 (m, 399.103-ylmethylsulfanyl]-4-ethyl-4H- 1H), 7.66 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.60 (m, 2H), 7.41 (m, 2H), 6.78 (s, 1H),4.65 (s, 2H), 4.07 (q, 2H), 1.40 (t, 3H). 456 2-Methyl-4-[3-(4-methyl-5-8.73 (d, 1H), 7.81 (s, thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.75 (s,2H), ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.51 (m, 2H), 4.60 (s, 2H),5-yl]-pyridine 3.71 (s, 3H) 2.68 (s, 3H). 4574-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.73 (d, 1H), 7.82 (s,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.76 (d, 1H),[1,2,4]oxadiazol-5-yl]-2-methyl- 7.54 (d, 1H), 7.48 (d, 1H), pyridine7.29 (m, 1H), 4.68 (s, 2H), 4.16 (m, 2H), 2.68 (s, 3H), 1.41 (t, 3H).458 5-(4-Ethyl-5-thiophen-2-yl-4H- 7.78 (d, 1H), 7.53 (t, 376.00[1,2,4]triazol-3-ylsulfanylmethyl)-3- 2H), 7.48 (d, 1H),thiophen-2-yl-[1,2,4]oxadiazole 7.18 (m, 2H), 4.74 (s, 2H), 4.17 (m,2H), 1.41 (t, 3H). 459 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (d, 2H),8.09 (m, 418.10 [1,2,4]oxadiazol-3- 1H), 7.58 (m, 3H),ylmethylsulfanyl]-4-ethyl-4H- 7.24 (m, 1H), 4.73 (s, 2H),[1,2,4]triazol-3-yl}-pyridine 4.13 (m, 2H), 1.41 (t, 3H). 4604-[3-(4-Ethyl-5-pyridin-4-yl-4H- 8.82 (d, 2H), 8.75 (d,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.84 (s, 1H),[1,2,4]oxadiazol-5-yl]-2-methyl- 7.76 (d, 1H), 7.60 (d, 2H), pyridine4.74 (s, 2H), 4.13 (m, 2H), 1.41 (t, 3H). 461 3-{5-[5-(3-Chloro-phenyl)-8.11 (s, 1H), 7.97 (m, [1,2,4]oxadiazol-3- 3H), 7.83 (d, 1H),ylmethylsulfanyl]-4-methyl-4H- 7.63 (m, 3H), 7.50 (t,[1,2,4]triazol-3-yl}-benzonitrile 1H), 4.63 (s, 2H) and 3.68 (s, 3H) 4625-(3-Chloro-phenyl)-3-[5-(3-chloro- 8.11 (s, 1H), 8.00 (d,phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.67 (m, 1H),3-ylsulfanylmethyl]- 7.50 (m, 5H), 4.61 (s, 2H) [1,2,4]oxadiazole and3.66 (s, 3H). 463 5-(3-Chloro-phenyl)-3-[5-(4-chloro- 8.11 (s, 1H), 8.01(d, phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.55 (m, 6H),3-ylsulfanylmethyl]- 4.61 (s, 2H) and 3.64 (s, 3H). [1,2,4]oxadiazole464 4-{5-[5-(2,5-Dichloro-phenyl)- 8.80 (dd, 2H), 8.05 (m,[1,2,4]oxadiazol-3- 1H), 7.59 (m, 2H), ylmethylsulfanyl]-4-ethyl-4H-7.47 (s, 2H), 4.73 (s, 2H), [1,2,4]triazol-3-yl}-pyridine 4.11 (m, 2H),1.32 (m, 3H). 465 5-(2,5-Dichloro-phenyl)-3-(4-ethyl- 8.06 (dd, 1H),7.50 (m, 5-thiophen-2-yl-4H-[1,2,4]triazol-3- 4H), 7.19 (dd, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 4.68 (s, 2H), 4.17 (q, 2H), 1.39 (t,3H). 466 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 8.80 (dd, 2H), 7.79 (m,406.10 5-thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.60 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.28 (m, 1H), 4.68 (s, 2H), 4.11 (q,2H), 1.39 (t, 3H). 467 4-{5-[5-(2,5-Difluoro-phenyl)- 7.80 (m, 1H), 7.52(m, [1,2,4]oxadiazol-3- 1H), 7.48 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.20 (m, 4H), 4.68 (s, 2H), [1,2,4]triazol-3-yl}-pyridine 4.17 (m, 2H),1.40 (t, 3H). 468 5-(2,5-Dichloro-phenyl)-3-(4-ethyl- 8.07 (dd, 1H),7.71 (dd, 5-thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.49 (m, 4H),ylsulfanylmethyl)-[1,2,4]oxadiazole 4.69 (s, 2H), 4.12 (m, 2H), 1.38 (t,3H). 469 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 7.80 (m, 1H), 7.72 (m,406.10 5-thiophen-3-yl-4H-[1,2,4]triazol-3- 1H), 7.49 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.28 (m, 2H), 4.68 (s, 2H), 4.12 (q,2H), 1.37 (t, 3H). 470 4-{5-[5-(3-Chloro-phenyl)- 8.80 (dd, 2H), 8.11(m, [1,2,4]oxadiazol-3- 1H), 7.99 (m, 1H),ylmethylsulfanyl]-4-propyl-4H- 7.57 (m, 3H), 7.48 (t, 1H),[1,2,4]triazol-3-yl}-pyridine 4.70 (s, 2H), 3.99 (q, 2H), 1.72 (m, 2H),0.91 (t, 3H). 471 4-{5-[5-(2-Fluoro-5-methyl- 8.80 (dd, 2H), 7.87 (dd,phenyl)-[1,2,4]oxadiazol-3- 1H), 7.58 (m, 2H),ylmethylsulfanyl]-4-propyl-4H- 7.39 (m, 1H), 7.15 (q, 1H),[1,2,4]triazol-3-yl}-pyridine 4.70 (s, 2H), 4.01 (m, 2H), 2.40 (s, 3H),1.70 (m, 2H), 0.87 (t, 3H). 472 3-(4-Ethyl-5-thiophen-2-yl-4H- 7.91 (d,1H), 7.67 (d, 376.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.52 (d,1H), thiophen-2-yl-[1,2,4]oxadiazole 7.48 (d, 1H), 7.20 (m, 2H), 4.62(s, 2H), 4.18 (m, 2H), 1.38 (t, 3H). 473 3-(4-Methyl-5-thiophen-3-yl-4H-7.90 (s, 1H), 7.74 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.67(d, 1H), thiophen-2-yl-[1,2,4]oxadiazole 7.52 (m, 2H), 7.21 (m, 1H),4.60 (s, 2H), 3.71 (s, 3H) 2.68 (s, 3H). 4744-[4-Methyl-5-(3-thiophen-3-yl- 8.82 (d, 2H), 8.05 (s,[1,2,4]oxadiazol-5- 1H), 7.61 (m, 3H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.44 (m, 1H), 4.73 (s, 2H),3-yl]-pyridine 3.70 (s, 3H). 475 5-(4-Methyl-5-thiophen-3-yl-4H- 8.05(s, 1H), 7.73 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.62 (d,1H), thiophen-3-yl-[1,2,4]oxadiazole 7.51 (s, 2H), 7.44 (m, 1H), 4.66(s, 2H), 3.68 (s, 3H). 476 5-(4-Ethyl-5-thiophen-2-yl-4H- 8.05 (d, 1H),7.62 (d, 376.10 [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.53 (d, 1H),thiophen-3-yl-[1,2,4]oxadiazole 7.47 (d, 1H), 7.44 (m, 1H), 7.19 (m,1H), 4.75 (s, 2H), 4.15 (m, 2H), 1.40 (t, 3H). 4775-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.18 (d, 1H), 8.03 (d, 401.00[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.51 (m, 1H),[1,2,4]oxadiazol-5-yl]-thiophene-3- 7.46 (m, 1H), 7.18 (m, 1H),carbonitrile 4.63 (s, 2H), 4.16 (q, 2H), 1.40 (t, 3H). 4785-(3-Chloro-phenyl)-3-[5-(2-fluoro- 8.13 (s, 1H), 8.01 (d,phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.52 (m, 4H),3-ylsulfanylmethyl]- 7.34 (t, 1H), 7.27 (m, 1H), [1,2,4]oxadiazole 4.63(s, 2H) and 3.54 (s, 3H). 479 5-(3-Chloro-phenyl)-3-[5-(3-fluoro- 8.11(s, 1H), 8.00 (d, 403.00 phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.52(m, 5H), 3-ylsulfanylmethyl]- 7.27 (m, 1H), 4.62 (s, 2H)[1,2,4]oxadiazole and 3.66 (s, 3H). 4805-(3-Chloro-phenyl)-3-[5-(4-fluoro- 8.11 (s, 1H), 8.00 (d, 403.10phenyl)-4-methyl-4H-[1,2,4]triazol- 1H), 7.59 (m, 4H),3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.22 (m, H), [1,2,4]oxadiazole 4.61(s, 2H) and 3.64 (s, 3H). 481 3-(5-Benzo[b]thiophen-2-yl-4- 8.11 (s,1H), 8.01 (d, methyl-4H-[1,2,4]triazol-3- 1H), 7.87 (m, 2H),ylsulfanylmethyl)-5-(3-chloro- 7.72 (s, 1H), 7.58 (d, 1H),phenyl)-[1,2,4]oxadiazole 7.45 (m, 3H), 4.60 (s, 2H) and 3.85 (s, 3H).482 5-(3-Chloro-phenyl)-3-[5-(3- 8.12 (s, 1H), 8.01 (d,methoxy-phenyl)-4-methyl-4H- 1H), 7.59 (dd, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.44 (t, 1H),[1,2,4]oxadiazole 7.2 (m, 2H), 7.05 (dd, 1H), 4.60 (s, 2H), 3.88 (s, 3H)and 3.65 (s, 3H). 483 5-(3-Chloro-phenyl)-3-[5-(4- 8.12 (s, 1H), 8.01(d, 415.00 methoxy-phenyl)-4-methyl-4H- 1H), 7.59 (m, 3H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.49 (t, 1H), 7.03 (d, 2H),[1,2,4]oxadiazole 4.59 (s, 2H), 3.89 (s, 3H) and 3.63 (s, 3H). 4843-(4-Ethyl-5-furan-2-yl-4H- 7.86 (dd, 1H), 7.59 (m, 386.10[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.37 (m, 1H),(2-fluoro-5-methyl-phenyl)- 7.14 (m, 2H), 6.58 (q, 1H),[1,2,4]oxadiazole 4.63 (s, 2H), 4.26 (q, 2H), 2.39 (s, 3H), 1.37 (t,3H). 485 3-(4-Ethyl-5-furan-2-yl-4H- 7.91 (m, 2H), 7.59 (m, 368.20[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.40 (m, 2H),m-tolyl-[1,2,4]oxadiazole 7.10 (q, 1H), 6.58 (q, 1H), 4.61 (s, 2H), 4.24(q, 2H), 2.43 (s, 3H), 1.36 (t, 3H). 4863-(4-Ethyl-5-trifluoromethyl-4H- 7.97 (m, 1H), 7.47 (m,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.16 (t, 1H),(2-fluoro-5-methyl-phenyl)- 4.72 (d, 2H), 4.16 (m, 2H),[1,2,4]oxadiazole 2.41 (d, 3H), 1.37 (m, 3H). 4873-[5-(2-Fluoro-5-methyl-phenyl)- (CD3OD as [1,2,4]oxadiazol-3- solvent):8.72 (m, 2H), ylmethylsulfanyl]-5-pyridin-4-yl- 8.17 (m, 2H), 7.86 (dd,[1,2,4]triazol-4-ylamine 1H), 7.49 (m, 1H), 7.23 (dd, 1H), 4.59 (s, 2H),2.35 (s, 3H). 488 3-[5-(2-Fluoro-5-methyl-phenyl)- (CD3OD as[1,2,4]oxadiazol-3- solvent): 8.05 (s, 1H),ylmethylsulfanyl]-5-thiophen-2-yl- 7.84 (dd, 1H), 7.69 (m,[1,2,4]triazol-4-ylamine 1H), 7.47 (m, 1H), 7.22 (m, 2H), 4.52 (s, 2H),2.33 (s, 3H). 489 3-Pyridin-4-yl-5-(5-m-tolyl- (CD3OD as[1,2,4]oxadiazol-3- solvent): 8.73 (dd, 2H),ylmethylsulfanyl)-[1,2,4]triazol-4- 8.17 (dd, 2H), 7.89 (m, ylamine 2H),7.46 (m, 2H), 4.58 (s, 2H), 2.389 (s, 3H). 4903-Thiophen-2-yl-5-(5-m-tolyl- (CD3OD as [1,2,4]oxadiazol-3- solvent):8.05 (dd, 1H), ylmethylsulfanyl)-[1,2,4]triazol-4- 7.87 (d, 2H), 7.70(dd, ylamine 1H), 7.45 (m, 2H), 7.23 (q, 1H), 4.50 (s, 2H), 2.39 (s,3H). 491 3-(4-Ethyl-5-furan-2-yl-4H- 8.23 (m, 1H), 7.66 (m, 360.10[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.60 (m, 1H),thiophen-3-yl-[1,2,4]oxadiazole 7.47 (m, 1H), 7.11 (m, 1H), 6.60 (m,1H), 4.61 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). 4925-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (m, 1H), 8.00 (m, 389.00furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.59 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.51 (t, 1H), 7.12 (m, 1H), 6.60 (m,1H), 4.63 (s, 2H), 4.26 (q, 2H), 1.38 (t, 3H). 4934-[3-(4-Ethyl-5-furan-2-yl-4H- 8.73 (d, 1H), 7.82 (s,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (m, 1H),[1,2,4]oxadiazol-5-yl]-2-methyl- 7.60 (m, 1H), 7.12 (m, 1H), pyridine6.60 (m, 1H), 4.65 (s, 2H), 4.26 (q, 2H), 2.68 (s, 3H), 1.39 (t, 3H).494 5-(2,5-Difluoro-phenyl)-3-(4-ethyl- 7.80 (m, 1H), 7.61 (m, 390.095-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.29 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.12 (m, 1H), 6.60 (m, 1H), 4.65 (s,2H), 4.28 (q, 2H), 1.39 (t, 3H). 495 4-[4-Ethyl-5-(5-thiophen-3-yl- 8.81(m, 2H), 7.63 (m, 371.00 isoxazol-3-ylmethylsulfanyl)-4H- 1H), 7.59 (m,2H), [1,2,4]triazol-3-yl]-pyridine 7.41 (m, 2H), 6.58 (s, 1H), 4.63 (s,2H), 4.06 (q, 2H), 1.38 (t, 3H). 496 4-Ethyl-3-furan-2-yl-5-(5-thiophen-7.77 (m, 1H), 7.60 (m, 359.10 3-yl-isoxazol-3-ylmethylsulfanyl)- 1H)7.40 (m, 2H), 4H-[1,2,4]triazole 7.10 (m, 1H), 6.60 (m, 1H), 6.55 (s,1H), 4.58 (s, 2H), 4.21 (q, 2H), 1.38 (t, 3H). 4975-(3-Chloro-phenyl)-3-[5-(3,5- 8.12 (s, 1H), 8.01 (d,dichloro-phenyl)-4-ethyl-4H- 1H), 7.60 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.54 (s, 3H), 7.47 (t, 1H),[1,2,4]oxadiazole 4.69 (s, 2H), 4.06 (q, 2H) and 1.36 (t, 3H). 4985-(3-Chloro-phenyl)-3-(4-ethyl-5-p- 8.13 (s, 1H), 8.01 (d,tolyl-4H-[1,2,4]triazol-3- 1H), 7.53 (m, 4H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.20 (d, 2H), 4.68 (s, 2H), 4.03 (q,3H), 2.45 (s, 1H) and 1.32 (t, 3H). 4995-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (s, 1H), 8.00 (d,m-tolyl-4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.29-7.50 (m, 5H), 4.66 (s, 2H),4.02 (q, 2H), 2.45 (s, 1H) and 1.32 (t, 3H). 5005-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.52 (s, 1H), 8.40 (d,(3-nitro-phenyl)-4H-[1,2,4]triazol- 1H), 8.12 (s, 1H),3-ylsulfanylmethyl]- 8.05 (dd, 2H), 7.76 (t, [1,2,4]oxadiazole 1H), 7.60(d, 1H), 7.50 (t, 1H), 4.72 (s, 2H), 4.10 (q, 2H) and 1.41 (t, 3H). 5014-{5-[3-(3-Chloro-phenyl)-isoxazol- 7.80 (m, 2H), 7.78 (m,5-ylmethylsulfanyl]-4-methyl-4H- 1H), 7.65 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.59 (m, 2H), 7.40 (m, 2H), 6.65 (s, 1H),4.67 (s, 2H), 3.64 (s, 3H). 502 5-(3-Chloro-phenyl)-3-[5-(2,5- 8.14 (s,1H), 8.02 (d, difluoro-phenyl)-4-ethyl-4H- 1H), 7.60 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (t, 1H), 7.32 (m, 1H),[1,2,4]oxadiazole 7.23 (m, 2H), 4.70 (s, 2H), 3.96 (q, 2H) and 1.27 (t,3H). 503 5-(3-Chloro-phenyl)-3-[5-(3-chloro- 8.11 (s, 1H), 8.06 (d,phenyl)-4-ethyl-4H-[1,2,4]triazol-3- 1H), 7.63 (s, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazole 7.58 (d, 1H), 7.49 (m, 4H), 7.23 (m,2H), 4.68 (s, 2H), 4.04 (q, 2H) and 1.34 (t, 3H). 5045-(3-Chloro-phenyl)-3-[5-(4-chloro- 8.13 (s, 1H), 8.01 (d,phenyl)-4-ethyl-4H-[1,2,4]triazol-3- 1H), 7.3 (m, 6H), 4.68 (s,ylsulfanylmethyl]-[1,2,4]oxadiazole 2H), 4.03 (q, 2H) and 1.34 (t, 3H).505 4-{5-[5-(3-Chloro-phenyl)-oxazol- 8.78 (d, 2H), 7.55 (m,2-ylmethylsulfanyl]-4-ethyl-4H- 3H), 7.44 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.29 (m, 3H), 4.69 (s, 2H), 4.04 (q, 2H)and 1.34 (t, 3H). 506 3-[5-(3-Chloro-phenyl)-oxazol-2- 7.55 (s, 1H),7.50 (d, 404.00 ylmethylsulfanyl]-4-ethyl-5- 1H), 7.44 (m, 2H),thiophen-2-yl-4H-[1,2,4]triazole 7.28 (m, 3H), 7.18 (dd, 1H), 4.64 (s,2H), 4.10 (q, 2H) and 1.35 (t, 3H). 507 3-[5-(3-Chloro-phenyl)-oxazol-2-7.58 (s, 1H), 7.53 (s, 388.00 ylmethylsulfanyl]-4-ethyl-5-furan- 1H),7.40 (m, 1H), 2-yl-4H-[1,2,4]triazole 7.27 (m, 3H), 7.10 (d, 1H), 6.68(d, 1H), 4.62 (s, 2H), 4.19 (q, 2H) and 1.33 (t, 3H). 5085-(2-Chloro-5-methyl-phenyl)-3-(4- 7.83 (s, 1H), 7.53 (d,ethyl-5-thiophen-2-yl-4H- 1H), 7.44 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.32 (d, 1H), 7.18 (t, 2H),[1,2,4]oxadiazole 4.63 (s, 2H), 4.17 (q, 2H), 2.37 (s, 3H), 1.38 (t,3H). 509 4-{5-[3-(3-Chloro-phenyl)-isoxazol- 8.80 (m, 2H), 7.78 (m,5-ylmethylsulfanyl]-4-ethyl-4H- 1H), 7.66 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 7.57 (m, 2H), 7.41 (m, 2H), 6.67 (s, 1H),4.71 (s, 2H), 4.03 (q, 2H), 1.36 (t, 3H). 5103-[3-(3-Chloro-phenyl)-isoxazol-5- 7.78 (s, 1H), 7.64 (m, 404.00ylmethylsulfanyl]-4-ethyl-5- 1H) 7.52 (m, 1H),thiophen-2-yl-4H-[1,2,4]triazole 7.41 (m, 3H), 7.18 (m, 1H), 6.65 (s,1H), 4.66 (s, 2H), 4.08 (q, 2H), 1.36 (t, 3H). 5113-[3-(3-Chloro-phenyl)-isoxazol-5- 7.77 (s, 1H), 7.64 (d, 388.10ylmethylsulfanyl]-4-ethyl-5-furan- 1H), 7.59 (m, 1H),2-yl-4H-[1,2,4]triazole 7.39 (m, 2H), 7.10 (m, 1H), 6.62 (s, 1H), 6.59(m, 1H), 4.65 (s, 2H), 4.17 (q, 2H), 1.35 (t, 3H). 5124-{5-[5-(2-Fluoro-5-methyl- phenyl)-isoxazol-3-ylmethylsulfanyl]-4-methyl-4H- [1,2,4]triazol-3-yl}-pyridine 5135-(2,5-Dichloro-thiophen-3-yl)-3- (DMSO-D6 as solvent):(4-ethyl-5-thiophen-2-yl-4H- 7.82 (dd, 1H), 7.65 (d,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.58 (m, 1H), [1,2,4]oxadiazole7.25 (m, 1H), 4.60 (s, 2H), 4.16 (q, 2H), 1.24 (t, 3H). 5144-{5-[5-(2,5-Dichloro-thiophen-3- 8.78 (d, 2H), 7.71 (d,yl)-[1,2,4]oxadiazol-3- 2H), 7.68 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H-4.67 (s, 2H), 4.10 (q, 2H), [1,2,4]triazol-3-yl}-pyridine 1.21 (t, 3H).515 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.81 (m, 2H), 7.73 (m,phenyl)-isoxazol-3- 1H), 7.60 (m, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.21 (m, 1H), 7.07 (m, 1H),3-yl}-pyridine 6.76 (m, 1H), 4.63 (s, 2H), 4.02 (q, 2H), 2.40 (s, 3H),1.38 (t, 3H). 516 4-Ethyl-3-[5-(2-fluoro-5-methyl- 7.71 (d, 1H), 7.53(m, phenyl)-isoxazol-3- 1H), 7.47 (m, 1H),ylmethylsulfanyl]-5-thiophen-2-yl- 7.46 (m, 2H), 7.07 (m, 1H),4H-[1,2,4]triazole 6.77 (d, 1H), 4.63 (s, 2H), 4.12 (q, 2H), 2.40 (s,3H), 1.39 (t, 3H). 517 4-Ethyl-3-[5-(2-fluoro-5-methyl- 7.72 (d, 1H),7.60 (m, phenyl)-isoxazol-3- 1H), 7.10 (m, 1H),ylmethylsulfanyl]-5-furan-2-yl-4H- 7.05 (m, 2H), 6.77 (d, 1H),[1,2,4]triazole 6.60 (m, 1H), 4.61 (s, 2H), 4.21 (q, 2H), 2.39 (s, 3H),1.38 (t, 3H). 518 5-(3-Chloro-phenyl)-3-(4-ethyl-5- 8.11 (s, 1H), 8.01(d, 391.00 trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.60 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.50 (t, 1H), 4.72 (s, 2H), 4.12 (q,2H) and 1.42 (t, 3H). 519 3-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.05 (s,1H), 7.94 (d, trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.50 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.43 (t, 1H), 4.83 (s, 2H), 4.13 (q,2H) and 1.44 (t, 3H). 520 3-(4-Ethyl-5-trifluoromethyl-4H- 8.23 (s, 1H),7.65 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.48 (m, 1H),thiophen-3-yl-[1,2,4]oxadiazole 4.69 (s, 2H), 4.12 (q, 2H) and 1.41 (t,3H). 521 5-(4-Ethyl-5-trifluoromethyl-4H- 8.05 (s, 1H), 7.61 (d,[1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.43 (m, 1H),thiophen-3-yl-[1,2,4]oxadiazole 4.81 (s, 2H), 4.12 (q, 2H) and 1.43 (t,3H). 522 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (d, 1H), 8.00 (d,(3-fluoro-phenyl)-4H-[1,2,4]triazol- 1H), 7.52 (m, 4H),3-ylsulfanylmethyl]- 7.25 (m, 2H), 4.67 (s, 2H), [1,2,4]oxadiazole 4.06(q, 2H), 1.31 (t, 3H). 523 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.10 (s,1H), 7.99 (d, (4-fluoro-phenyl)-4H-[1,2,4]triazol- 1H), 7.59 (m, 4H),3-ylsulfanylmethyl]- 7.48 (t, 1H), 7.22 (d, 1H), [1,2,4]oxadiazole 4.67(s, 2H), 4.01 (q, 2H), 1.30 (t, 3H). 5243-(4-Ethyl-5-trifluoromethyl-4H- 7.91 (s, 1H), 7.68 (d,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.21 (m, 1H),thiophen-2-yl-[1,2,4]oxadiazole 4.67 (s, 2H), 4.13 (q, 2H) and 1.41 (t,3H). 525 3-{3-[5-(3-Chloro-thiophen-2-yl)-4- 8.35 (m, 2H), 7.89 (d,ethyl-4H-[1,2,4]triazol-3- 1H), 7.87 (t, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.58 (d, 1H), 7.09 (d, 1H),5-yl}-benzonitrile 4.70 (s, 2H), 4.00 (q, 2H), 1.27 (t, 3H). 5264-{5-[5-(3-Chloro-phenyl)- 8.82 (d, 2H), 8.01 (d, 400.10[1,3,4]oxadiazol-2- 1H), 9.93 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.59 (m, 2H), 7.52 (m, 1H), [1,2,4]triazol-3-yl}-pyridine 7.47 (m, 1H),4.83 (s, 2H), 4.11 (q, 2H), 1.40 (t, 3H). 5272-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.00 (s, 1H), 7.89 (d, 389.00furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.60 (m, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazole 7.50 (m, 1H), 7.44 (m, 1H), 7.13 (m,1H), 6.60 (m, 1H), 4.76 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 5285-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (s, 1H), 8.01 (d,(4-methoxy-phenyl)-4H- 1H), 7.57 (m, 3H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.05 (d, 2H),[1,2,4]oxadiazole 4.67 (s, 2H), 4.02 (q, 2H), 3.89 (s, 3H), 1.31 (t,3H). 529 5-(3-Chloro-phenyl)-3-[5-(2-fluoro- 8.12 (s, 1H), 8.02 (d,5-methyl-phenyl)-4-furan-2- 1H), 7.58 (d, 1H),ylmethyl-4H-[1,2,4]triazol-3- 7.52 (d, 1H), 7.35 (d, 2H),ylsulfanylmethyl]-[1,2,4]oxadiazole 7.23 (s, 1H), 7.22 (d, 1H), 6.19 (s,1H), 6.04 (s, 1H), 5.13 (s, 2H), 4.61 (s, 2H), 2.37 (s, 3H). 5304-[3-(4-Ethyl-5-trifluoromethyl-4H- 8.74 (d, 1H), 7.81 (s,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.74 (d, 1H),[1,2,4]oxadiazol-5-yl]-2-methyl- 4.74 (s, 2H), 4.12 (q, 2H) pyridine2.69 (s, 1H) and 1.42 (t, 3H). 531 3-(4-Ethyl-5-trifluoromethyl-4H- 7.70(d, 1H), 7.60 (s, [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.44 (t,1H), (3-methoxy-phenyl)- 7.16 (d, 1H), 4.70 (s, 2H), [1,2,4]oxadiazole4.12 (q, 2H), 3.90 (s, 3H) and 1.41 (t, 3H). 5325-(4-Ethyl-5-trifluoromethyl-4H- 7.63 (d, 1H), 7.56 (s,[1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.39 (t, 1H),(3-methoxy-phenyl)- 7.07 (d, 1H), 4.82 (s, 2H), [1,2,4]oxadiazole 4.12(q, 2H) and 1.42 (t, 3H). 533 5-(4-Ethyl-5-trifluoromethyl-4H- 7.77 (s,1H), 7.52 (d, [1,2,4]triazol-3-ylsulfanylmethyl)-3- 1H), 7.16 (m, 1H),thiophen-2-yl-[1,2,4]oxadiazole 4.79 (s, 2H), 4.13 (q, 2H) and 1.42 (t,3H). 534 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.07 (dd, 1H), 7.56 (m,ethyl-5-trifluoromethyl-4H- 1H), 7.24 (dd, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 4.73 (s, 2H), 4.13 (q, 2H) and[1,2,4]oxadiazole 1.42 (t, 3H). 535 3-[3-(4-Ethyl-5-trifluoromethyl-4H-8.40 (s, 1H), 8.34 (d, 381.10 [1,2,4]triazol-3-ylsulfanylmethyl)- 1H),7.91 (d, 1H), [1,2,4]oxadiazol-5-yl]-benzonitrile 7.01 (t, 1H), 4.73 (s,2H), 4.12 (q, 2H) and 1.42 (t, 3H). 5363-[5-(3-Chloro-phenyl)-isoxazol-3- 7.75 (s, 1H), 7.63 (m,ylmethylsulfanyl]-4-ethyl-5- 1H), 7.40 (m, 2H),trifluoromethyl-4H-[1,2,4]triazole 6.73 (s, 1H), 4.65 (s, 2H), 4.07 (q,2H) and 1.40 (t, 3H). 537 3-[5-(3-Chloro-phenyl)-oxazol-2- 7.58 (s, 1H),7.46 (d, ylmethylsulfanyl]-4-ethyl-5- 1H), 7.32 (d, 3H),trifluoromethyl-4H-[1,2,4]triazole 4.74 (s, 2H), 4.09 (q, 2H) and 1.39(t, 3H). 538 4-Ethyl-3-(5-thiophen-3-yl- 7.78 (s, 1H), 7.39 (m,isoxazol-3-ylmethylsulfanyl)-5- 1H), 6.53 (d, 1H),trifluoromethyl-4H-[1,2,4]triazole 4.63 (s, 2H), 4.07 (q, 2H) and 1.39(t, 3H). 539 4-{3-[5-(3-Fluoro-phenyl)-4- 8.73 (d, 1H), 7.83 (s,methyl-4H-[1,2,4]triazol-3- 1H), 7.76 (d, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.47 (m, 3H), 7.27 (s, 1H),5-yl}-2-methyl-pyridine 4.65 (s, 2H), 3.67 (s, 3H), 2.69 (s, 3H). 5404-{3-[5-(3-Chloro-phenyl)-4- 8.74 (d, 1H), 7.82 (s,methyl-4H-[1,2,4]triazol-3- 1H), 7.67 (d, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.56 (d, 1H), 7.51 (m, 1H),5-yl}-2-methyl-pyridine 7.48 (m, 1H), 7.46 (s, 1H), 4.65 (s, 2H), 3.67(s, 3H), 2.69 (s, 3H). 541 4-{3-[5-(4-Chloro-phenyl)-4- 8.73 (d, 1H),7.82 (s, methyl-4H-[1,2,4]triazol-3- 1H), 7.75 (d, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.63 (d, 2H), 7.51 (d, 2H),5-yl}-2-methyl-pyridine 4.65 (s, 2H), 3.65 (s, 3H), 2.69 (s, 3H). 5424-{3-[5-(4-Methoxy-phenyl)-4- 8.73 (d, 1H), 7.83 (s,methyl-4H-[1,2,4]triazol-3- 1H), 7.45 (d, 1H),ylsulfanylmethyl]-[1,2,4]oxadiazol- 7.61 (d, 2H), 7.04 (d, 2H),5-yl}-2-methyl-pyridine 4.62 (s, 2H), 3.89 (s, 3H), 3.64 (s, 3H), 2.69(s, 3H). 543 4-[3-(4-Ethyl-5-p-tolyl-4H- 8.74 (d, 1H), 7.85 (s,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.77 (d, 1H),[1,2,4]oxadiazol-5-yl]-2-methyl- 7.51 (d, 2H), 7.32 (d, 2H), pyridine4.70 (s, 2H), 4.03 (q, 2H), 2.70 (s, 3H), 2.45 (s, 3H), 1.31 (t, 3H).544 3-(4-Ethyl-5-thiophen-2-yl-4H- (DMSO-D6 as solvent): 388.10[1,2,4]triazol-3-ylsulfanylmethyl)-5- 7.93 (m, 1H), 7.86 (m,(3-fluoro-phenyl)-[1,2,4]oxadiazole 2H), 7.80 (m, 1H), 7.67 (m, 2H),7.25 (m, 1H), 4.61 (s, 2H), 4.16 (q, 2H), 1.24 (t, 3H). 5454-{4-Ethyl-5-[5-(3-fluoro-phenyl)- 8.78 (bs, 2H), 7.92 (m, 383.10[1,2,4]oxadiazol-3- 2H), 7.71 (d, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.68 (m, 1H), 7.27 (m, 1H),3-yl}-pyridine 4.70 (s, 2H), 4.10 (q, 2H), 1.39 (t, 3H). 5465-(3-Chloro-phenyl)-3-[5-(3,5- 8.11 (s, 1H), 8.01 (d,difluoro-phenyl)-4-ethyl-4H- 1H), 7.58 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.50 (t, 1H), 7.21 (m, 2H),[1,2,4]oxadiazole 7.00 (t, 1H), 4.68 (s, 2H), 4.07 (q, 2H), 1.35 (t,3H). 547 5-(3-Chloro-phenyl)-3-[5-(2,6- 8.12 (s, 1H), 8.02 (d,difluoro-phenyl)-4-ethyl-4H- 1H), 7.59 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (d, 1H), 7.41 (d, 1H),[1,2,4]oxadiazole 7.04 (d, 1H), 4.73 (s, 2H), 4.21 (q, 2H), 1.42 (t,3H). 548 2-[3-(4-Ethyl-5-thiophen-2-yl-4H- 9.89 (s, 1H), 7.70 (s, 399.90[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.56 (d, 1H),[1,2,4]oxadiazol-5-yl]-4-methyl- 7.54 (d, 1H), 7.30 (m, 1H), phenol 7.18(m, 1H), 6.98 (d, 1H), 4.66 (s, 2H), 4.12 (q, 2H), 2.34 (s, 3H), 1.37(t, 3H). 549 3-{1-[5-(3-Chloro-phenyl)-isoxazol- 7.73 (bs, 1H), 7.59 (m,401.10 3-yl]-ethylsulfanyl}-4-ethyl-5- 2H), 7.41 (m, 2H),furan-2-yl-4H-[1,2,4]triazole 7.10 (dd, 1H), 6.59 (m, 2H), 5.05 (q, 1H),4.13 (q, 2H), 1.91 (d, 3H), 1.27 (t, 3H). 5504-(5-{1-[5-(3-Chloro-phenyl)- 8.8 (dd, 2H), 7.74 (bs,isoxazol-3-yl]-ethylsulfanyl}-4- 1H), 7.63 (m, 1H),ethyl-4H-[1,2,4]triazol-3-yl)- 7.57 (dd, 2H), 7.40 (m, 2H), pyridine6.62 (s, 2H), 5.15 (q, 1H), 4.05 (q, 2H), 1.95 (d, 3H), 1.34 (t, 3H).551 3-[5-(4-Butoxy-phenyl)-4-ethyl-4H- 8.12 (s, 1H), 8.01 (d,[1,2,4]triazol-3-ylsulfanylmethyl]-5- 1H), 7.58 (d, 1H),(3-chloro-phenyl)-[1,2,4]oxadiazole 7.52 (d, 2H), 7.49 (d, 1H), 7.01 (d,2H), 4.69 (s, 2H), 4.02 (q, 4H), 1.82 (m, 2H), 1.51 (q, 2H), 1.32 (t,3H), 1.01 (t, 3H). 552 3-(5-Benzo[1,3]dioxol-5-yl-4-ethyl- 8.12 (s, 1H),8.00 (d, 4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),ylsulfanylmethyl)-5-(3-chloro- 7.51 (d, 1H), 7.09 (d, 2H),phenyl)-[1,2,4]oxadiazole 6.96 (s, 1H), 6.08 (s, 2H), 4.67 (s, 2H), 4.02(q, 2H), 1.31 (t, 3H). 553 3-(4-Ethyl-5-thiophen-2-yl-4H- 8.11 (s, 1H),7.48 (m, 391.90 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H), 7.16 (t, 1H),(2-methyl-thiazol-4-yl)- 4.63 (s, 2H), 4.13 (q, 2H), [1,2,4]oxadiazole2.82 (s, 3H), 1.37 (t, 3H). 554 3-(4-Ethyl-5-thiophen-2-yl-4H- (DMSO-D6as solvent): [1,2,4]triazol-3-ylsulfanylmethyl)-5- 8.21 (m, 2H), 7.51(m, (4-fluoro-phenyl)-[1,2,4]oxadiazole 2H), 7.21 (m, 3H), 4.63 (s, 2H),4.16 (q, 2H), 1.38 (t, 3H). 555 4-Ethyl-3-{1-[5-(2-fluoro-5-methyl- 7.71(dd, 1H), 7.59 (dd, phenyl)-isoxazol-3-yl]- 1H), 7.26 (m, 1H),ethylsulfanyl}-5-furan-2-yl-4H- 7.06 (m, 2H), 6.66 (d, 1H),[1,2,4]triazole 6.58 (dd, 1H), 5.06 (q, 1H), 4.13 (q, 2H), 2.39 (s, 3H),1.91 (d, 3H), 1.28 (t, 3H). 556 4-(4-Ethyl-5-{1-[5-(2-fluoro-5- 8.79(dd, 2H), 7.71 (dd, 410.10 methyl-phenyl)-isoxazol-3-yl]- 1H), 7.59 (dd,2H), ethylsulfanyl}-4H-[1,2,4]triazol-3- 7.23 (m, 1H), 7.06 (m, 1H),yl)-pyridine 6.64 (d, 1H), 5.15 (q, 1H), 4.01 (q, 2H), 2.39 (s, 3H),1.94 (d, 3H), 1.30 (t, 3H). 557 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.11(s, 1H), 8.00 (d, (3-methyl-3H-imidazol-4-yl)-4H- 1H), 7.66 (s, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.58 (d, 1H), 7.52 (t, 1H),[1,2,4]oxadiazole 7.37 (s, 1H), 4.69 (s, 2H), 4.09 (q, 2H), 3.93 (s,3H), 1.37 (t, 3H). 558 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (s, 1H),8.01 (d, (1-methyl-1H-imidazol-2-yl)-4H- 1H), 7.57 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.17 (s, 1H),[1,2,4]oxadiazole 7.04 (s, 1H), 4.69 (s, 2H), 4.56 (q, 2H), 4.12 (s,3H), 1.40 (t, 3H). 559 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.12 (s, 1H),8.01 (d, (1-methyl-1H-imidazol-4-yl)-4H- 1H), 7.65 (s, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.57 (d, 1H), 7.48 (d, 2H),[1,2,4]oxadiazole 4.60 (s, 2H), 4.50 (q, 2H), 3.79 (s, 3H), 1.36 (t,3H). 560 4-{5-[5-(3-Chloro-phenyl)-4- 8.81 (bs, 2H), 7.70 (m,methyl-isoxazol-3- 1H), 7.61 (m, 3H), ylmethylsulfanyl]-4-ethyl-4H- 7.44(m, 2H), 4.65 (s, 2H), [1,2,4]triazol-3-yl}-pyridine 4.09 (q, 2H), 2.31(s, 3H), 1.40 (t, 3H). 561 3-[5-(3-Chloro-phenyl)-4-methyl- 7.70 (s,1H), 7.60 (m, isoxazol-3-ylmethylsulfanyl]-4- 2H), 7.43 (m, 2H),ethyl-5-furan-2-yl-4H- 7.10 (m, 1H), 6.59 (m, 1H), [1,2,4]triazole 4.59(s, 2H), 4.23 (q, 2H), 2.28 (s, 3H), 1.38 (t, 3H). 5623-(4-Ethyl-5-thiophen-2-yl-4H- 7.61 (d, 1H), 7.49 (m,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H), 7.22 (m, 2H),(4-methyl-thiophen-2-yl)- 4.59 (s, 2H), 4.16 (q, [1,2,4]oxadiazole 2H),2.32 (s, 3H), 1.38 (t, 3H). 563 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.13(s, 1H), 8.01 (d, (3-methyl-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.52 (d, 1H), 7.45 (d, 1H),[1,2,4]oxadiazole 7.02 (d, 1H), 4.69 (s, 2H), 3.97 (q, 2H), 2.32 (s,3H), 1.28 (t, 3H). 564 5-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.11 (s, 1H),8.01 (d, (5-methyl-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (t, 1H), 7.28 (s, 1H),[1,2,4]oxadiazole 6.83 (d, 1H), 4.64 (s, 2H), 4.14 (q, 2H), 2.56 (s,3H), 1.39 (t, 3H). 565 4-{5-[4-Chloro-5-(3-chloro-phenyl)- 8.81 (d, 2H),7.99 (m, isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.90 (m, 1H),ethyl-4H-[1,2,4]triazol-3-yl}- 7.60 (m, 2H), 7.48 (m, 2H), pyridine 4.65(s, 2H), 4.10 (q, 2H), 1.39 (t, 3H). 5663-[4-Chloro-5-(3-chloro-phenyl)- 7.99 (s, 1H), 7.90 (m,isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.60 (m, 1H),ethyl-5-furan-2-yl-4H- 7.47 (m, 2H), 7.12 (m, 1H), [1,2,4]triazole 6.60(m, 1H), 4.59 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 5672-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.11 (s, 1H), 8.00 (d,[1,2,4]oxadiazol-3- 1H), 7.58 (d, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.52 (d, 1H), 7.40 (d, 2H), [1,2,4]triazol-3-yl}-6-methyl- 4.71 (s, 2H),4.10 (q, pyridine 2H), 2.64 (s, 3H), 1.40 (t, 3H). 5683-[5-(5-Bromo-furan-2-yl)-4-ethyl- 8.11 (s, 1H), 7.99 (d,4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H), ylsulfanylmethyl]-5-(3-chloro-7.51 (t, 1H), 7.07 (d, 1H), phenyl)-[1,2,4]oxadiazole 6.52 (d, 1H), 4.64(s, 2H), 4.23 (q, 2H), 1.40 (t, 3H). 5692-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.59 (d, 1H), 8.10 (s,[1,2,4]oxadiazol-3- 1H), 8.00 (d, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.66 (s, 1H), 7.59 (d, 1H), [1,2,4]triazol-3-yl}-pyridine 7.54 (d, 1H),7.50 (d, 1H), 4.72 (s, 2H), 4.11 (q, 2H), 1.42 (t, 3H). 5702-Chloro-4-{5-[5-(3-chloro-phenyl)- 8.11 (s, 1H), 8.00 (d, 464.10[1,2,4]oxadiazol-3- 1H), 7.58 (d, 1H), ylmethylsulfanyl]-4-ethyl-4H-7.50 (t, 1H), 7.24 (s, 1H), [1,2,4]triazol-3-yl}-6-methoxy- 6.91 (s,1H), 4.70 (s, pyridine 2H), 4.08 (q, 2H), 4.02 (s, 3H), 1.39 (t, 3H).571 2-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.02 (s, 1H), 7.76 (d,[1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.47 (m, 3H),[1,2,4]oxadiazol-5-yl]-4-methyl- 7.17 (t, 1H), 4.68 (s, 2H),benzonitrile 4.19 (q, 2H), 2.51 (s, 3H), 1.39 (t, 3H). 5725-(3-Chloro-phenyl)-3-[4-ethyl-5- 8.14 (s, 1H), 8.03 (d,(3-methoxy-thiophen-2-yl)-4H- 1H), 7.58 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.50 (d, 1H), 7.44 (d, 1H),[1,2,4]oxadiazole 6.94 (1H), 4.67 (s, 2H), 4.03 (q, 2H), 3.88 (s, 3H),1.29 (t, 3H). 573 3-[5-(5-Chloro-thiophen-3-yl)- 7.61 (m, 1H), 7.52 (d,393.10 isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.21 (d, 1H),ethyl-5-furan-2-yl-4H- 7.11 (m, 1H), 7.61 (m, 1H), [1,2,4]triazole 6.55(s, 1H), 4.57 (s, 2H), 4.21 (q, 2H), 1.38 (t, 3H). 5743-[3-(4-Ethyl-5-furan-2-yl-4H- 8.21 (m, 1H), 8.04 (dd,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.59 (m, 2H),[1,2,4]oxadiazol-5-yl]-5-fluoro- 7.10 (dd, 1H), 6.59 (dd, 1H),benzonitrile 4.64 (s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 5754-Ethyl-3-(5-phenyl-isoxazol-3- 7.77 (m, 2H), 7.53 (d,ylmethylsulfanyl)-5-thiophen-2-yl- 1H), 7.47 (m, 4H), 4H-[1,2,4]triazole7.19 (dd, 1H), 6.71 (s, 1H), 4.61 (s, 2H), 4.12 (q, 2H) and 1.39 (t,3H). 576 4-Methyl-3-(5-phenyl-isoxazol-3- 7.77 (m, 3H), 7.50 (m,ylmethylsulfanyl)-5-thiophen-3-yl- 5H), 6.69 (s, 1H), 4H-[1,2,4]triazole4.56 (s, 2H) and 3.67 (s, 3H) 577 4-Ethyl-3-furan-2-yl-5-(5-phenyl- 7.77(m, 2H), 7.61 (s, isoxazol-3-ylmethylsulfanyl)-4H- 1H), 7.46 (m, 3H),[1,2,4]triazole 7.14 (d, 1H), 6.69 (s, 1H), 6.60 (d, 1H), 4.60 (s, 2H),4.22 (q, 2H) and 1.38 (t, 3H). 578 4-[4-Ethyl-5-(5-phenyl-isoxazol-3-8.82 (w, 2H), 7.77 (m, ylmethylsulfanyl)-4H-[1,2,4]triazol- 2H), 7.61(d, 2H), 3-yl]-pyridine 7.45 (m, 3H), 6.71 (s, 1H), 4.65 (s, 2H), 4.06(q, 2H) and 1.39 (t, 3H). 579 4-[4-Methyl-5-(5-phenyl-isoxazol- 8.81 (w,2H), 7.77 (m, 3-ylmethylsulfanyl)-4H- 2H), 7.63 (d, 2H),[1,2,4]triazol-3-yl]-pyridine 7.46 (m, 3H), 6.70 (s, 1H), 4.60 (s, 2H)and 3.68 (s, 3H). 580 2-(4-Ethyl-5-furan-2-yl-4H- 7.80 (m, 2H), 7.70 (m,368.10 [1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.35 (m, 2H),m-tolyl-[1,3,4]oxadiazole 7.13 (m, 2H), 6.60 (m, 1H), 4.74 (s, 2H), 4.23(q, 2H), 2.40 (s, 3H), 1.36 (t, 3H). 581 4-[4-Methyl-5-(5-m-tolyl- 8.81(m, 2H), 7.80 (m, 365.10 [1,3,4]oxadiazol-2- 2H), 7.61 (d, 2H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.39 (m, 2H), 4.74 (s, 2H),3-yl]-pyridine 3.71 (s, 3H), 2.4 (s, 3H). 582 4-[4-Ethyl-5-(5-m-tolyl-8.81 (d, 2H), 7.81 (m, 379.10 [1,3,4]oxadiazol-2- 2H), 7.58 (m, 2H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.37 (m, 2H), 4.81 (s, 2H),3-yl]-pyridine 4.41 (q, 2H), 2.42 (s, 3H), 1.33 (t, 3H). 5834-{5-[5-(5-Chloro-thiophen-3-yl)- 8.80 (d, 2H), 7.98 (m, 405.90[1,2,4]oxadiazol-3- 1H), 7.58 (d, 2H), ylmethylsulfanyl]-4-ethyl-4H-7.46 (d, 1H), 4.66 (s, 2H), [1,2,4]triazol-3-yl}-pyridine 4.10 (q, 2H),1.38 (t, 3H). 584 3-[3-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (bs, 2H), 8.46(m, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.91 (m, 1H),[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.59 (d, 2H), 7.43 (t, 1H),benzonitrile 4.74 (s, 2H), 4.12 (q, 2H), 1.41 (t, 3H). 5853-[3-(4-Ethyl-5-furan-2-yl-4H- 8.45 (dd, 1H), 7.91 (m, 397.10[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.59 (d, 1H),[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.43 (t, 1H), 7.10 (d, 1H),benzonitrile 6.58 (dd, 1H), 4.65 (s, 2H), 4.27 (q, 2H), 1.39 (t, 3H).586 3-[3-(4-Ethyl-5-thiophen-2-yl-4H- 8.45 (dd, 1H), 7.90 (m,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.47 (m, 3H),[1,2,4]oxadiazol-5-yl]-4-fluoro- 7.18 (t, 1H), 4.68 (s, 2H),benzonitrile 4.17 (q, 2H), 1.41 (t, 3H). 5873-[3-(4-Ethyl-5-furan-2-yl-4H- 8.41 (m, 2H), 7.89 (d, 379.10[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.69 (d, 1H),[1,2,4]oxadiazol-5-yl]-benzonitrile 7.13 (m, 1H), 6.60 (m, 1H), 4.65 (s,2H), 4.27 (q, 2H), 1.40 (t, 3H). 588 3-[5-(4-Ethyl-5-furan-2-yl-4H- 8.36(m, 2H), 7.80 (t, 379.10 [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.62(m, 2H), [1,2,4]oxadiazol-3-yl]-benzonitrile 7.15 (m, 1H), 6.61 (m, 1H),4.78 (s, 2H), 4.2 (q, 2H), 1.40 (t, 3H). 5893-[3-(4-Methyl-5-trifluoromethyl- 8.41 (m, 2H), 7.90 (m,4H-[1,2,4]triazol-3- 1H), 7.72 (t, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 4.68 (s, 2H), 3.73 (s, 3H).5-yl]-benzonitrile 590 5-(5-Chloro-2-fluoro-phenyl)-3-(4- 8.08 (m, 1H),7.58 (m, 394.90 methyl-5-trifluoromethyl-4H- 1H), 7.25 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 4.67 (s, 2H), 3.74 (s, 3H).[1,2,4]oxadiazole 591 2-Chloro-4-[3-(4-ethyl-5-furan-2-yl- 8.63 (m, 1H),8.02 (m, 390.00 4H-[1,2,4]triazol-3- 1H), 7.89 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.61 (m, 1H), 7.14 (m, 1H),5-yl]-pyridine 6.61 (m, 1H), 4.67 (s, 2H), 4.27 (q, 2H), 1.40 (t, 3H).592 2-Chloro-4-[3-(5-furan-2-yl-4- 8.63 (d, 1H), 8.00 (d,methyl-4H-[1,2,4]triazol-3- 1H), 7.88 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.62 (d, 1H), 7.14 (d, 1H),5-yl]-pyridine 6.61 (m, 1H), 4.60 (s, 2H), 3.82 (s, 3H). 5932-(3-Chloro-phenyl)-5-[4-methyl-5- 7.98 (m, 2H), 7.89 (d,(2-methyl-thiazol-4-yl)-4H- 1H), 7.49 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.44 (m, 1H), 4.69 (s, 2H),[1,3,4]oxadiazole 3.92 (s, 3H), 2.77 (s, 3H). 5942-(3-Chloro-phenyl)-5-(4-methyl-5- 8.91 (s, 1H), 8.24 (s,thiazol-4-yl-4H-[1,2,4]triazol-3- 1H), 7.98 (s, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazole 7.91 (d, 1H), 7.49 (m, 1H), 7.43 (m,1H), 4.72 (s, 2H), 3.96 (s, 3H). 595 2-(3-Chloro-phenyl)-5-(5-furan-2-8.00 (s, 1H), 7.89 (d, yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (s,1H), ylsulfanylmethyl)-[1,3,4]oxadiazole 7.53 (m, 1H), 7.43 (m, 1H),7.12 (d, 1H), 6.60 (d of d, 1H), 4.68 (s, 2H), 3.80 (s, 3H). 5962-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.00 (s, 1H), 7.90 (d,trifluoromethyl-4H-[1,2,4]triazol-3- 1H), 7.52 (m, 2H),ylsulfanylmethyl)-[1,3,4]oxadiazole 4.86 (s, 2H), 4.13 (q, 2H), 1.42 (t,3H). 597 4-{4-Ethyl-5-[5-(4-methyl- 8.79 (d, 2H), 7.68 (s,thiophen-2-yl)-[1,2,4]oxadiazol-3- 1H), 7.59 (d, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.23 (m, 1H), 4.63 (s, 2H),3-yl}-pyridine 4.10 (q, 2H), 2.32 (d, 3H), 1.37 (t, 3H). 5983-(4-Ethyl-5-furan-2-yl-4H- 7.67 (d, 1H), 7.59 (m, 374.00[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.2 (s, 1H), 7.09 (d,(4-methyl-thiophen-2-yl)- 1H), 6.58 (dd, 1H), [1,2,4]oxadiazole 4.56 (s,2H), 4.24 (q, 2H), 2.32 (s, 3H), 1.36 (t, 3H). 5993-(3-Chloro-phenyl)-5-(4-ethyl-5- 8.02 (m, 1H), 7.91 (m,furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.57 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.35 (m, 2H), 7.08 (d, 1H), 6.56(dd, 1H), 4.72 (s, 2H), 4.22 (q, 2H), 2.32 (s, 3H), 1.36 (t, 3H). 6004-{5-[3-(3-Chloro-phenyl)- 8.79 (dd, 2H), [1,2,4]oxadiazol-5- 8.02 (m,1H), 7.92 (m, 1H), ylmethylsulfanyl]-4-ethyl-4H- 7.57 (dd, 2H),[1,2,4]triazol-3-yl}-pyridine 7.42 (m, 2H), 4.80 (s, 2H), 4.08 (q, 2H),1.38 (t, 3H). 601 4-{4-Ethyl-5-[5-(3-nitro-phenyl)- 8.87 (m, 3H), 8.42(m, [1,3,4]oxadiazol-2- 2H), 7.75 (t, 1H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.66 (d, 2H), 4.88 (s, 2H),3-yl}-pyridine 4.15 (q, 2H), 1.45 (t, 3H). 6022-(4-Ethyl-5-furan-2-yl-4H- 8.87 (t, 1H), 8.39 (m,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 2H), 7.73 (t, 1H),(3-nitro-phenyl)-[1,3,4]oxadiazole 7.61 (m, 1H), 7.15 (m, 1H), 6.61 (m,1H), 4.28 (q, 2H), 1.78 (s, 2H), 1.41 (t, 3H). 6034-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.79 (d, 2H), 7.78 (m, 411.003-ylmethylsulfanyl]-4-cyclopropyl- 3H), 7.66 (m, 1H),4H-[1,2,4]triazol-3-yl}-pyridine 7.39 (m, 2H), 6.84 (s, 1H), 4.69 (s,2H), 3.27 (m, 1H), 1.20 (q, 2H), 0.83 (m, 2H). 6043-[5-(3-Chloro-phenyl)-isoxazol-3- 7.77 (m, 1H), 7.65 (m, 428.20ylmethylsulfanyl]-4-ethyl-5-(4- 1H), 7.56 (m, 2H),methoxy-phenyl)-4H-[1,2,4]triazole 7.41 (m, 2H), 7.04 (m, 2H), 6.79 (s,1H), 4.61 (s, 2H), 3.97 (q, 2H), 3.89 (s, 3H), 1.32 (t, 3H). 6055-(3-Chloro-phenyl)-3-[1-(4- 8.08 (m, 1H), 7.96 (dd, 404.92methyl-5-thiophen-2-yl-4H- 1H), 7.45 (m, 4H),[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 7.17 (m, 1H), 4.93 (q, 1H),[1,2,4]oxadiazole 3.67 (s, 3H), 1.91 (d, 3H). 6065-(3-Chloro-phenyl)-3-[1-(4-ethyl- 8.1 (d, 1H), 7.98 (d, 1H), 418.905-thiophen-2-yl-4H-[1,2,4]triazol-3- 7.51 (m, 4H), 7.17 (t,ylsulfanyl)-ethyl]-[1,2,4]oxadiazole 1H), 5.11 (q, 1H), 4.11 (q, 2H),1.93 (d, 3H), 1.34 (t, 3H). 607 4-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (dd,2H), 400.07 [1,2,4]oxadiazol-3-yl]- 8.08 (m, 1H), 7.98 (dd, 1H),ethylsulfanyl}-4-methyl-4H- 7.59 (m, 3H), 7.46 (t,[1,2,4]triazol-3-yl)-pyridine 1H), 5.05 (q, 1H), 3.66 (s, 3H), 1.94 (d,3H). 608 4-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (dd, 2H), 414.05[1,2,4]oxadiazol-3-yl]- 8.10 (m, 1H), 7.99 (dd, 1H),ethylsulfanyl}-4-ethyl-4H- 7.58 (m, 3H), 7.47 (t,[1,2,4]triazol-3-yl)-pyridine 1H), 5.20 (q, 1H), 4.06 (q, 2H), 1.96 (d,3H), 1.33 (t, 3H). 609 3-[5-(4-Ethyl-5-pyridin-4-yl-4H- 8.84 (s, 2H),8.30 (m, [1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.85 (m, 1H),[1,3,4]oxadiazol-2-yl]-benzonitrile 7.66 (m, 3H), 4.84 (s, 2H), 4.14 (q,2H), 1.43 (t, 3H). 610 3-[5-(4-Ethyl-5-furan-2-yl-4H- 8.27 (m, 2H), 7.82(m, [1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.62 (m, 2H),[1,3,4]oxadiazol-2-yl]-benzonitrile 7.18 (t, 1H), 6.62 (m, 1H), 4.79 (s,2H), 4.27 (q, 2H), 1.40 (t, 3H). 611 3-[5-(4-Methyl-5-pyridin-4-yl-4H-8.83 (d, 2H), 8.31 (m, [1,2,4]triazol-3-ylsulfanylmethyl)- 2H), 7.84 (m,4H), [1,3,4]oxadiazol-2-yl]-benzonitrile 4.81 (s, 2H), 3.77 (s, 3H). 6123-[5-(4-Cyclopropyl-5-pyridin-4-yl- 8.82 (s, 2H), 8.33 (m, 402.204H-[1,2,4]triazol-3- 2H), 7.86 (t, 3H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.67 (t, 1H), 4.91 (d, 2H),2-yl]-benzonitrile 1.24 (m, 3H), 0.88 (m, 2H). 6134-{5-[5-(3-Chloro-phenyl)- (CD3OD as solvent): [1,3,4]oxadiazol-2- 8.80(s (br), 2H), ylmethylsulfanyl]-4-methyl-4H- 7.96 (m, 2H), 7.81 (d, 2H),[1,2,4]triazol-3-yl}-pyridine 7.61 (m, 2H), 4.73 (s, 2H), 3.84 (s, 3H).614 4-{5-[5-(3-Chloro-phenyl)- (CD3OD as solvent): 412.16[1,3,4]oxadiazol-2- 8.75 (d, 2H), 8.02 (s,ylmethylsulfanyl]-4-cyclopropyl- 1H), 7.96 (d, 1H),4H-[1,2,4]triazol-3-yl}-pyridine 7.89 (d, 2H), 7.60 (m, 2H), 4.89 (s,2H), 3.59 (m, 1H), 1.21 (m, 2H), 0.84 (m, 2H). 6154-{5-[5-(5-Chloro-2-fluoro-phenyl)- 7.80 (m, 2H), 8.04 (m, 430.11[1,3,4]oxadiazol-2- 1H), 7.77 (d, 2H), ylmethylsulfanyl]-4-cyclopropyl-7.51 (m, 1H), 7.21 (t, 1H), 4H-[1,2,4]triazol-3-yl}-pyridine 4.92 (s,2H), 3.32 (m, 1H), 1.21 (m, 2H), 0.85 (m, 2H). 6162-(5-Chloro-2-fluoro-phenyl)-5-[4- 8.02 (m, 1H), 7.52 (m,ethyl-5-(4-methoxy-phenyl)-4H- 3H), 7.20 (t, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.04 (m, 2H), 4.81 (s, 2H),[1,3,4]oxadiazole 4.03 (q, 2H), 3.89 (s, 3H), 1.33 (t, 3H). 6174-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.83 (d, 2H), 8.03 (m,[1,3,4]oxadiazol-2- 1H), 7.65 (m, 2H), ylmethylsulfanyl]-4-methyl-4H-7.51 (m, 1H), 7.20 (t, 1H), [1,2,4]triazol-3-yl}-pyridine 4.78 (s, 2H),3.75 (s, 3H). 618 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (bs, 2H),8.02 (m, [1,3,4]oxadiazol-2- 1H), 7.61 (m, 2H),ylmethylsulfanyl]-4-ethyl-4H- 7.51 (m, 1H), 7.20 (t, 1H),[1,2,4]triazol-3-yl}-pyridine 4.85 (s, 2H), 4.13 (q, 2H), 1.41 (t, 3H).619 2-(3-Chloro-phenyl)-5-[4-ethyl-5- 8.01 (d of d collapsed,(4-methoxy-phenyl)-4H- 1H), 7.85 (d, 1H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.51 (m, 4H), 7.00 (d,[1,3,4]oxadiazole 2H), 4.79 (s, 2H), 4.00 (q, 2H), 3.88 (s, 3H), 1.30(t, 3H). 620 2-(3-Chloro-phenyl)-5-[1-(4-ethyl- 7.97 (s, 1H), 7.84 (d,5-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.58 (d, 1H),ylsulfanyl)-ethyl]-[1,3,4]oxadiazole 7.49 (m, 1H), 7.40 (m, 1H), 7.12(d, 1H), 6.59 (d of d, 1H), 5.16 (q, 1H), 4.17 (q, 2H), 2.02 (d, 3H),1.28 (t, 3H). 621 5-(5-Chloro-2-fluoro-phenyl)-3-[1- 8.06 (m, 1H), 7.54(m, (4-methyl-5-thiophen-2-yl-4H- 3H), 7.23 (m, 2H),[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 4.93 (q, 1H), 3.72 (s, 3H),[1,2,4]oxadiazole 1.91 (d, 3H). 622 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.79(dd, 2H), 418.10 phenyl)-[1,2,4]oxadiazol-3-yl]- 8.07 (dd, 1H), 7.62(dd, 2H), ethylsulfanyl}-4-methyl-4H- 7.54 (m, 1H), 7.21 (t,[1,2,4]triazol-3-yl)-pyridine 1H), 5.07 (q, 1H), 3.69 (s, 3H), 1.95 (d,3H). 623 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.79 (dd, 2H),phenyl)-[1,2,4]oxadiazol-3-yl]- 8.08 (m, 1H), 7.57 (m, 3H),ethylsulfanyl}-4-ethyl-4H- 7.22 (t, 1H), 5.21 (q,[1,2,4]triazol-3-yl)-pyridine 1H), 4.08 (q, 2H), 1.97 (d, 3H), 1.35 (t,3H). 624 2-Chloro-4-[3-(4-cyclopropyl-5- 8.83 (m, 2H), 8.65 (m,pyridin-4-yl-4H-[1,2,4]triazol-3- 1H), 8.05 (t, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.92 (t, 1H), 7.76 (t, 2H),5-yl]-pyridine 4.82 (2H), 3.31 (m, 1H), 1.23 (m, 2H), 0.86 (m, 2H). 6254-{5-[5-(2-Fluoro-5-methyl- 8.83 (t, 2H), 7.82 (m,phenyl)-[1,3,4]oxadiazol-2- 1H), 7.63 (m, 2H),ylmethylsulfanyl]-4-methyl-4H- 7.32 (m, 1H), 7.10 (m, 1H),[1,2,4]triazol-3-yl}-pyridine 4.75 (s, 2H), 3.73 (s, 3H), 2.39 (s, 3H),1.61 (d, 1H). 626 4-{4-Ethyl-5-[5-(2-fluoro-5-methyl- 8.82 (d, 2H), 7.82(m, 397.08 phenyl)-[1,3,4]oxadiazol-2- 1H), 7.59 (t, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.33 (m, 1H), 7.11 (m, 1H),3-yl}-pyridine 4.82 (s, 2H), 4.10 (m, 2H), 2.39 (s, 3H), 1.38 (t, 3H).627 4-{4-Cyclopropyl-5-[5-(2-fluoro-5- 8.80 (s, 2H), 7.84 (m, 409.15methyl-phenyl)-[1,3,4]oxadiazol-2- 1H), 7.76 (d, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.32 (m, 1H), 7.12 (q, 1H),3-yl}-pyridine 4.91 (s, 2H), 3.31 (m, 1H), 2.39 (d, 3H), 1.21 (m, 2H),0.84 (m, 2H). 628 2-(4-Ethyl-5-furan-2-yl-4H- 7.77 (m, 1H), 7.61 (m,[1,2,4]triazol-3-ylsulfanylmethyl)-5- 1H), 7.32 (d, 1H),(2-fluoro-5-methyl-phenyl)- 7.12 (m, 2H), 6.61 (m, 1H),[1,3,4]oxadiazole 4.76 (s, 2H), 4.26 (q, 2H), 2.37 (d, 3H), 1.23 (t,3H). 629 2-[4-Ethyl-5-(4-methoxy-phenyl)- 7.81 (m, 1H), 7.54 (m, 426.154H-[1,2,4]triazol-3- 2H), 7.32 (d, 1H), ylsulfanylmethyl]-5-(2-fluoro-5-7.11 (m, 1H), 7.03 (m, 2H), methyl-phenyl)-[1,3,4]oxadiazole 4.79 (s,2H), 4.02 (q, 2H), 3.89 (s, 3H), 2.37 (d, 3H), 1.31 (t, 3H). 6304-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (dd, 2H), 7.91 (dd, 417.02isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.60 (dd, 2H),ethyl-4H-[1,2,4]triazol-3-yl}- 7.38 (m, 1H), 7.15 (m, 1H), pyridine 6.86(d, 1H), 4.67 (s, 2H), 4.05 (q, 2H), 1.37 (t, 3H). 6314-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (dd, 2H), 7.91 (dd, 431.10phenyl)-isoxazol-3-yl]- 1H), 7.59 (dd, 2H), ethylsulfanyl}-4-ethyl-4H-7.38 (m, 1H), 7.15 (m, 1H), [1,2,4]triazol-3-yl)-pyridine 6.74 (d, 1H),5.20 (q, 1H), 4.05 (q, 2H), 1.95 (d, 3H), 1.34 (t, 3H). 6324-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.82 (dd, 2H), 7.91 (dd, 403.10isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.63 (dd, 2H),methyl-4H-[1,2,4]triazol-3-yl}- 7.39 (m, 1H), 7.15 (m, 1H), pyridine6.85 (d, 1H), 4.62 (s, 2H), 3.69 (s, 3H). 6334-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (dd, 2H), 7.91 (dd, 417.10phenyl)-isoxazol-3-yl]- 1H), 7.60 (dd, 2H), ethylsulfanyl}-4-methyl-4H-7.38 (m, 1H), 7.15 (m, 1H), [1,2,4]triazol-3-yl)-pyridine 6.72 (d, 1H),5.06 (q, 1H), 3.64 (s, 3H), 1.93 (d, 3H). 6344-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.80 (dd, 2H), 7.92 (dd, 429.10isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.76 (dd, 2H),cyclopropyl-4H-[1,2,4]triazol-3-yl}- 7.38 (m, 1H), 7.15 (m, 1H),pyridine 6.95 (d, 1H), 4.71 (s, 2H), 3.27 (m, 1H), 1.18 (m, 2H), 0.82(m, 2H). 635 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.78 (dd, 2H), 7.92 (dd,443.20 phenyl)-isoxazol-3-yl]- 1H), 7.76 (dd, 2H),ethylsulfanyl}-4-cyclopropyl-4H- 7.38 (m, 1H), 7.15 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 6.85 (d, 1H), 5.40 (q, 1H), 3.24 (m, 1H),1.98 (d, 3H), 1.88 (m, 2H), 0.80 (m, 2H). 6363-[5-(5-Chloro-2-fluoro-phenyl)- 7.90 (dd, 1H), 7.60 (dd,isoxazol-3-ylmethylsulfanyl]-4- 1H), 7.39 (m, 1H),ethyl-5-furan-2-yl-4H- 7.11 (m, 2H), 6.85 (d, 1H), [1,2,4]triazole 6.59(dd, 1H), 4.62 (s, 2H), 4.20 (q, 2H), 1.38 (t, 3H). 6373-{1-[5-(5-Chloro-2-fluoro-phenyl)- 7.88 (dd, 1H), 7.59 (dd,isoxazol-3-yl]-ethylsulfanyl}-4- 1H), 7.39 (m, 1H),ethyl-5-furan-2-yl-4H- 7.11 (m, 2H), 6.74 (d, 1H), [1,2,4]triazole 6.58(dd, 1H), 5.08 (q, 1H), 4.20 (q, 2H), 1.92 (d, 3H), 1.34 (t, 3H). 6384-(5-{1-[5-(3-Chloro-phenyl)- 1.96 (d, 3H) 3.61 (s, 3H)[1,3,4]oxadiazol-2-yl]- 5.10 (q, 1H) 7.38 (t,ethylsulfanyl}-4-methyl-4H- 1H) 7.47 (m, 1H)[1,2,4]triazol-3-yl)-pyridine 7.54 (m, 2H) 7.84 (m, 1H) 7.93 (m, 1H)8.74 (d, 2H) 639 4-(5-{1-[5-(3-Chloro-phenyl)- 8.80 (bs, 2H), 7.99 (m,414.10 [1,3,4]oxadiazol-2-yl]- 1H), 7.90 (m, 1H),ethylsulfanyl}-4-ethyl-4H- 7.58 (d, 2H), 7.51 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 7.46 (t, 1H), 5.31 (q, 1H), 4.06 (q, 2H),2.04 (d, 3H), 1.31 (t, 3H). 640 4-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (bs,2H), 8.03 (m, 426.07 [1,3,4]oxadiazol-2-yl]- 1H), 7.94 (d, 1H),ethylsulfanyl}-4-cyclopropyl-4H- 7.76 (d, 2H), 7.51 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 7.45 (t, 1H), 7.54 (q, 1H), 3.25 (m, 1H),2.06 (d, 3H), 1.19 (m, 2H), 0.81 (m, 2H). 6415-(5-Chloro-2-fluoro-phenyl)-3-(5- 8.06 (dd, 1H), 7.60 (d,furan-2-yl-4-methyl-4H- 1H), 7.55 (m, 1H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.22 (t, 1H), 7.09 (d, 1H),[1,2,4]oxadiazole 6.58 (m, 1H), 4.55 (s, 2H), 3.81 (s, 3H). 6425-(5-Chloro-2-fluoro-phenyl)-3-(5- 8.06 (dd, 1H), 7.89 (d,furan-3-yl-4-methyl-4H- 1H), 7.55 (m, 2H),[1,2,4]triazol-3-ylsulfanylmethyl)- 7.22 (t, 1H), 6.88 (dd, 1H),[1,2,4]oxadiazole 4.55 (s, 2H), 3.67 (s, 3H). 6434-Chloro-2-[3-(4-ethyl-5-thiophen- 10.08 (s, 1H), 7.88 (d,2-yl-4H-[1,2,4]triazol-3- 1H), 7.47 (m, 3H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.17 (t, 1H), 7.06 (d, 1H),5-yl]-phenol 4.68 (s, 2H), 4.14 (q, 2H), 1.38 (t, 3H). 6442-Chloro-4-[5-(4-methyl-5-pyridin- 8.83 (d, 2H), 8.60 (m,4-yl-4H-[1,2,4]triazol-3- 1H), 7.94 (m, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.85 (m, 1H), 7.62 (m, 2H),2-yl]-pyridine 4.82 (s, 2H), 3.75 (s, 3H). 6452-Chloro-4-[5-(4-ethyl-5-pyridin-4- 8.82 (d, 2H), 8.60 (m,yl-4H-[1,2,4]triazol-3- 1H), 7.94 (m, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.86 (m, 1H), 7.59 (m, 2H),2-yl]-pyridine 4.87 (s, 2H), 4.12 (q, 2H), 1.43 (t, 3H). 6462-Chloro-4-[5-(4-cyclopropyl-5- 8.81 (d, 2H), 8.60 (m,pyridin-4-yl-4H-[1,2,4]triazol-3- 1H), 7.96 (m, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.86 (m, 1H), 7.75 (m, 2H),2-yl]-pyridine 4.92 (s, 2H), 3.32 (m, 1H), 1.21 (m, 2H), 0.87 (q, 2H).647 2-Chloro-4-[5-(4-ethyl-5-furan-2-yl- 8.57 (m, 1H), 7.92 (m,4H-[1,2,4]triazol-3- 1H), 7.81 (m, 1H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 7.61 (m, 1H), 7.12 (m, 1H),2-yl]-pyridine 6.61 (m, 1H), 4.79 (s, 2H), 4.26 (q, 2H), 1.40 (t, 3H).648 2-Chloro-4-{5-[4-ethyl-5-(4- 8.59 (m, 1H), 7.94 (m,methoxy-phenyl)-4H-[1,2,4]triazol- 1H), 7.84 (m, 1H),3-ylsulfanylmethyl]- 7.55 (m, 2H), 7.05 (m, 2H),[1,3,4]oxadiazol-2-yl}-pyridine 4.83 (s, 2H), 4.02 (q, 2H), 1.34 (t,3H). 649 2-(3-Chloro-phenyl)-5-{1-[5-(4- 8.00 (m, 1H), 7.87 (d,methoxy-phenyl)-4-methyl-4H- 1H), 7.53 (m, 3H),[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 7.42 (t, 1H), 7.01 (m, 2H),[1,3,4]oxadiazole 5.07 (q, 1H), 3.88 (s, 3H), 3.54 (s, 3H), 2.00 (d,3H). 650 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.81 (bs, 2H), 8.01 (m,phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.63 (d, 2H),ethylsulfanyl}-4-methyl-4H- 7.50 (m, 1H), 7.18 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.17 (q, 1H), 3.69 (s, 3H), 2.02 (d, 3H).651 5-(5-Bromo-2-fluoro-phenyl)-3-(4- 8.20 (m, 1H), 7.65 (m,ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 1H), 7.60 (s, 1H),3-ylsulfanylmethyl)- 7.13 (m, 2H), 6.56 (m, 1H), [1,2,4]oxadiazole 4.64(s, 2H), 4.25 (q, 2H), 1.38 (t, 3H). 652 2-(3-Chloro-phenyl)-5-[5-(4-8.02 (d, 1H), 7.90 (d, methoxy-phenyl)-4-methyl-4H- 1H), 7.50 (m, 4H),[1,2,4]triazol-3-ylsulfanylmethyl]- 7.03 (d, 2H), 4.71 (s, 2H),[1,3,4]oxadiazole 3.88 (s, 3H), 3.61 (s, 3H). 6534-{5-[3-(3-Chloro-phenyl)- 8.79 (d, 2H), 8.09 (t, 412.07[1,2,4]oxadiazol-5- 1H), 7.97 (m, 1H), ylmethylsulfanyl]-4-cyclopropyl-7.76 (d, 2H), 7.45 (m, 2H), 4H-[1,2,4]triazol-3-yl}-pyridine 4.89 (s,2H), 3.30 (m, 1H), 1.22 (m, 2H), 0.86 (m, 2H). 6544-{5-[5-(3-Chloro-phenyl)- 8.78 (s, 2H), 8.14 (m, [1,2,4]oxadiazol-3-1H), 8.04 (m, 1H), ylmethylsulfanyl]-4-cyclopropyl- 7.77 (t, 2H), 7.54(m, 2H), 4H-[1,2,4]triazol-3-yl}-pyridine 4.79 (s, 2H), 3.29 (m, 1H),1.21 (m, 2H), 0.85 (d, 2H). 655 4-(5-{1-[5-(2-Fluoro-5-methyl- 8.79 (s,2H), 7.79 (t, phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.61 (t, 2H),ethylsulfanyl}-4-methyl-4H- 7.33 (m, 1H), 7.08 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.09 (m, 1H), 3.65 (s, 3H), 2.37 (s, 3H),2.02 (d, 3H). 656 4-(4-Ethyl-5-{1-[5-(2-fluoro-5- 8.81 (m, 2H), 8.23 (m,methyl-phenyl)-[1,3,4]oxadiazol-2- 1H), 7.79 (d, 2H),yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.32 (m, 1H), 7.09 (m, 1H),3-yl)-pyridine 5.28 (m, 1H), 4.07 (m, 2H), 2.37 (s, 3H), 2.04 (d, 3H),1.24 (m, 3H). 657 4-(4-Cyclopropyl-5-{1-[5-(2-fluoro- 8.78 (m, 2H), 7.82(d, 5-methyl-phenyl)-[1,3,4]oxadiazol- 1H), 7.74 (d, 2H),2-yl]-ethylsulfanyl}-4H- 7.31 (m, 1H), 7.11 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.51 (m, 1H), 3.23 (m, 1H), 2.38 (s, 3H),2.06 (d, 3H), 1.16 (m, 2H), 0.78 (m, 2H). 6584-(4-Cyclopropylmethyl-5-{1-[5-(2- 8.83 (m, 2H), 7.78 (m,fluoro-5-methyl-phenyl)- 1H), 7.59 (m, 2H), [1,3,4]oxadiazol-2-yl]- 7.33(m, 1H), 7.10 (m, 1H), ethylsulfanyl}-4H-[1,2,4]triazol-3- 5.26 (m, 1H),3.90 (m, yl)-pyridine 2H), 2.37 (s, 3H), 2.03 (d, 3H), 0.92 (m, 1H),0.48 (m, 2H), 0.21 (m, 2H). 659 2-(2-Fluoro-5-methyl-phenyl)-5-{1- 7.98(s, 1H), 7.75 (m, [4-methyl-5-(2-methyl-thiazol-4- 1H), 7.31 (m, 1H),yl)-4H-[1,2,4]triazol-3-ylsulfanyl]- 7.08 (m, 1H), 5.03 (q, 1H),ethyl}-[1,3,4]oxadiazole 3.85 (s, 3H), 2.75 (s, 3H), 2.35 (s, 3H), 1.98(d, 3H). 660 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.80 (m, 2H), 8.01 (m,phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.58 (m, 2H),ethylsulfanyl}-4-ethyl-4H- 7.49 (m, 1H), 7.19 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.32 (q, 1H), 4.08 (q, 2H), 2.04 (d, 3H),1.35 (t, 3H). 661 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.79 (d, 2H), 8.03 (m,phenyl)-[1,3,4]oxadiazol-2-yl]- 1H), 7.75 (m, 2H),ethylsulfanyl}-4-cyclopropyl-4H- 7.50 (m, 1H), 7.20 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.55 (q, 1H), 3.26 (s, 1H), 2.06 (d, 3H),1.18 (m, 2H), 0.81 (m, 2H). 662 2-(5-Chloro-2-fluoro-phenyl)-5-[1- 8.97(m, 1H), 7.59 (m, (4-ethyl-5-furan-2-yl-4H- 1H), 7.47 (m, 1H),[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 7.17 (m, 1H), 7.12 (m, 1H),[1,3,4]oxadiazole 6.59 (m, 1H), 5.18 (q, 1H), 4.21 (q, 2H), 2.00 (d,3H), 1.33 (t, 3H). 663 2-(5-Chloro-2-fluoro-phenyl)-5-{1- 7.99 (s, 1H),7.96 (m, [4-methyl-5-(2-methyl-thiazol-4- 1H), 7.48 (m, 1H),yl)-4H-[1,2,4]triazol-3-ylsulfanyl]- 7.17 (t, 1H), 7.06 (q, 1H),ethyl}-[1,3,4]oxadiazole 3.86 (s, 3H), 2.75 (s, 3H), 1.98 (d, 3H). 6644-(4-Cyclopropylmethyl-5-{1-[5-(2- 8.78 (dd, 2H), 7.71 (dd,fluoro-5-methyl-phenyl)-isoxazol-3- 1H), 7.58 (dd, 2H),yl]-ethylsulfanyl}-4H-[1,2,4]triazol- 7.25 (m, 1H), 7.08 (m, 1H),3-yl)-pyridine 6.62 (d, 1H), 5.12 (q, 1H), 3.87 (dd, 2H), 2.40 (s, 3H),1.94 (d, 3H), 0.90 (m, 1H), 0.49 (m, 2H), 0.19 (m, 2H). 6654-(5-{1-[5-(3-Fluoro-phenyl)- 8.78 (bs, 2H), 7.92 (d,[1,2,4]oxadiazol-3-yl]- 1H), 7.80 (dd, 1H), ethylsulfanyl}-4-methyl-4H-7.60 (d, 2H), 7.50 (m, 1H), [1,2,4]triazol-3-yl)-pyridine 7.25 (m, 1H),5.05 (q, 2H), 3.65 (s, 3H), 1.94 (d, 3H). 6664-(4-Cyclopropyl-5-{1-[5-(3-fluoro- 8.76 (d, 2H), 7.95 (d,phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.85 (dd, 1H),ethylsulfanyl}-4H-[1,2,4]triazol-3- 7.75 (d, 2H), 7.50 (m, 1H),yl)-pyridine 7.25 (m, 1H), 5.45 (q, 2H), 3.20 (m, 1H), 1.98 (d, 3H) 1.22(m, 2H), 0.88 (m, 2H). 667 4-(5-{1-[5-(4-Methoxy-phenyl)-4- 8.65 (d,1H), 7.71 (s, methyl-4H-[1,2,4]triazol-3- 1H), 7.63 (d, 1H),ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.54 (d, 2H), 7.00 (d, 2H),2-yl)-2-methyl-pyridine 5.10 (q, 1H), 3.87 (s, 3H), 3.53 (s, 3H), 2.58(s, 3H), 2.00 (d, 3H). 668 4-(5-{1-[4-Ethyl-5-(4-methoxy- 8.65 (d, 1H),7.71 (s, phenyl)-4H-[1,2,4]triazol-3- 1H), 7.63 (d, 1H),ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.49 (d, 2H), 7.01 (d, 2H),2-yl)-2-methyl-pyridine 5.26 (q, 1H), 3.96 (q, 2H), 3.88 (s, 3H), 2.62(s, 3H), 2.02 (d, 3H), 1.24 (t, 3H). 6694-{5-[1-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (d, 2H), 8.67 (d,[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 1H), 7.73 (s, 1H),[1,3,4]oxadiazol-2-yl}-2-methyl- 7.65 (d, 1H), 7.55 (d, 2H), pyridine5.33 (q, 1H), 4.08 (q, 2H), 2.64 (s, 3H), 2.03 (d, 3H), 1.30 (t, 3H).670 4-{5-[1-(4-Cyclopropyl-5-pyridin-4- 8.77 (d, 2H), 8.68 (d,yl-4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 7.72 (m, 4H),ethyl]-[1,3,4]oxadiazol-2-yl}-2- 5.55 (q, 1H), 3.24 (m, 1H),methyl-pyridine 2.64 (s, 3H), 2.04 (d, 3H), 1.16 (m, 2H), 0.81 (m, 2H).671 4-{5-[1-(5-Furan-2-yl-4-methyl-4H- 8.61 (d, 1H), 7.57 (m,[1,2,4]triazol-3-ylsulfanyl)-ethyl]- 3H), 7.08 (d, 1H),[1,3,4]oxadiazol-2-yl}-2-methyl- 6.57 (d, 1H), 5.02 (q, 1H), pyridine3.70 (s, 3H), 1.96 (d, 3H). 672 2-(3-Chloro-phenyl)-5-{1-[4- 7.99 (s,1H), methyl-5-(2-methyl-thiazol-4-yl)- 7.94 (m, 1H), 7.86 (m, 1H),4H-[1,2,4]triazol-3-ylsulfanyl]- 7.48 (m, 1H), 7.39 (m,ethyl}-[1,3,4]oxadiazole 1H), 5.03 (q, 1H), 3.82 (t, 3H), 2.73 (d, 3H),1.98 (d, 3H). 673 3-(5-{1-[5-(3-Chloro-phenyl)- 8.88 (s, 1H), 8.76 (d,[1,3,4]oxadiazol-2-yl]- 1H), 8.00 (m, 2H), ethylsulfanyl}-4-methyl-4H-7.90 (d, 1H), 7.48 (m, 3H), [1,2,4]triazol-3-yl)-pyridine 5.14 (q, 1H),3.60 (s, 3H), 2.02 (d, 3H). 674 4-(5-{1-[5-(3-Chloro-phenyl)- 8.66 (d,1H), 7.99 (m, [1,3,4]oxadiazol-2-yl]- 1H), 7.88 (m, 1H),ethylsulfanyl}-4-methyl-4H- 7.51 (m, 1H), 7.43 (m, 2H),[1,2,4]triazol-3-yl)-2-methyl- 7.34 (d, 1H), 5.13 (q, pyridine 1H), 3.61(s, 3H), 2.63 (s, 3H), 2.00 (d, 3H). 675 4-(5-{1-[5-(3-Chloro-phenyl)-8.68 (dd, 2H), 8.05 (d, [1,2,4]oxadiazol-3-yl]- 1H), 7.92 (d, 1H),ethylsulfanyl}-4-cyclopropyl-4H- 7.67 (dd, 2H), 7.51 (d, 1H),[1,2,4]triazol-3-yl)-pyridine 7.37 (t, 1H) 5.37 (q, 1H), 3.18 (m, 1H),1.90 (d, 3H), 1.08 (m, 2H), 0.74 (m, 2H). 6765-(3-Chloro-phenyl)-3-{1-[5-(4- 8.01 (s, 1H), 7.90 (d,methoxy-phenyl)-4-methyl-4H- 1H), 7.50 (m, 3H),[1,2,4]triazol-3-ylsulfanyl]-ethyl}- 7.38 (t, 1H), 6.92 (d, 2H),[1,2,4]oxadiazole 4.88 (q, 1H) 3.78 (s, 3H), 3.47 (s, 3H), 1.83 (d, 3H).677 4-(5-{1-[5-(5-Chloro-2-fluoro- 8.70 (dd, 2H), 8.05 (m,phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.67 (m, 2H),ethylsulfanyl}-4-cyclopropyl-4H- 7.46 (m, 1H), 7.18 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.41 (q, 1H), 3.18 (m, 1H), 1.90 (d, 3H),1.08 (m, 2H), 0.74 (m, 2H). 678 5-(5-Chloro-2-fluoro-phenyl)-3-{1- 8.05(m, 1H), 7.56 (m, [5-(4-methoxy-phenyl)-4-methyl- 3H), 7.21 (t, 1H),4H-[1,2,4]triazol-3-ylsulfanyl]- 7.00 (m, 3H), 5.01 (q, 1H),ethyl}-[1,2,4]oxadiazole 3.85 (s, 3H), 3.56 (s, 3H), 1.90 (d, 3H). 6794-[5-(4-Ethyl-5-pyridin-4-yl-4H- 8.79 (d, 2H), 8.67 (d,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.75 (s, 1H),[1,3,4]oxadiazol-2-yl]-2-methyl- 7.67 (d, 1H), 7.56 (d, 2H), pyridine4.82 (s, 2H), 4.10 (q, 2H), 2.64 (s, 3H), 1.39 (t, 3H). 6804-[5-(4-Cyclopropyl-5-pyridin-4-yl- 8.78 (d, 3H), 8.68 (d,4H-[1,2,4]triazol-3- 1H), 7.74 (m, 4H),ylsulfanylmethyl)-[1,3,4]oxadiazol- 4.90 (s, 2H), 3.30 (m, 1H),2-yl]-2-methyl-pyridine 2.65 (s, 3H), 1.21 (m, 2H), 0.84 (m, 2H). 6814-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.79 (d, 2H), 8.12 (m,[1,2,4]oxadiazol-3- 1H), 7.76 (m, 2H), ylmethylsulfanyl]-4-cyclopropyl-7.57 (m, 1H), 7.25 (m, 1H), 4H-[1,2,4]triazol-3-yl}-pyridine 4.81 (s,2H), 3.31 (m, 1H), 1.20 (m, 2H), 0.85 (m, 2H). 6824-[5-(5-Furan-2-yl-4-methyl-4H- 8.66 (d, 1H), 7.72 (s,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H), 7.65 (d, 1H),[1,3,4]oxadiazol-2-yl]-2-methyl- 7.60 (d, 1H), 7.11 (d, 1H), pyridine6.60 (d of d, 1H), 4.70 (s, 2H), 3.80 (s, 3H), 2.64 (s, 3H). 6834-(5-{1-[5-(3-Chloro-phenyl)- 8.79 (bs, 2H), 7.98 (m,[1,3,4]oxadiazol-2-yl]- 1H), 7.88 (m, 1H), ethylsulfanyl}-4- 7.51 (m,4H), 5.30 (q, 1H), cyclopropylmethyl-4H- 3.90 (m, 2H), 2.05 (t,[1,2,4]triazol-3-yl)-pyridine 3H), 0.94 (ms, 1H), 0.50 (m, 2H), 0.19 (m,2H). 684 4-(5-{1-[5-(4-Fluoro-phenyl)-4- 8.66 (d, 1H), 7.72 (s,methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (m, 3H),ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.17 (m, 3H), 5.13 (q, 1H),2-yl)-2-methyl-pyridine 3.57 (s, 3H), 2.63 (s, 3H), 2.00 (d, 3H). 6854-(5-{1-[5-(3-Fluoro-phenyl)-4- 8.65 (d, 1H), 7.72 (s,methyl-4H-[1,2,4]triazol-3- 1H), 7.66 (d, 1H),ylsulfanyl]-ethyl}-[1,3,4]oxadiazol- 7.48-7.20 (m, 4H), 5.15 (q,2-yl)-2-methyl-pyridine 1H), 3.60 (s, 3H), 2.63 (s, 3H), 2.01 (d, 3H).686 3-[3-(4-Cyclopropyl-5-pyridin-4-yl- 8.77 (dd, 2H),4H-[1,2,4]triazol-3- 8.49 (dd, 1H), 7.90 (m, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.74 (dd, 2H), 7.43 (t,5-yl]-4-fluoro-benzonitrile 1H), 4.81 (s, 2H), 3.31 (m, 1H), 1.21 (m,2H), 0.83 (m, 2H). 687 4-Chloro-2-[3-(4-cyclopropyl-5- 10.15 (bs, 1H),8.77 (dd, pyridin-4-yl-4H-[1,2,4]triazol-3- 2H), 7.89 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.75 (dd, 2H), 7.45 (dd, 1H),5-yl]-phenol 7.06 (d, 1H), 4.79 (s, 2H), 3.29 (m, 1H), 1.21 (m, 2H),0.83 (m, 2H). 688 4-{4-Cyclopropyl-5-[5-(3-methoxy- 8.77 (dd, 2H), 7.72(m, phenyl)-[1,2,4]oxadiazol-3- 3H), 7.62 (dd, 1H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.43 (t, 1H), 7.14 (m, 1H),3-yl}-pyridine 4.77 (s, 2H), 3.88 (s, 3H), 3.28 (m, 1H), 1.17 (m, 2H),0.84 (m, 2H). 689 4-{4-Cyclopropyl-5-[5-(2-fluoro-5- 8.7 (q, 2H), 7.81(d, methyl-phenyl)-[1,2,4]oxadiazol-3- 1H), 7.7 (q, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.29 (m, 1H), 7.1 (t, 1H),3-yl}-pyridine 4.71 (s, 2H), 3.23 (m, 1H), 2.32 (s, 3H), 1.11 (m, 2H),0.76 (m, 2H) 690 4-{4-Cyclopropyl-5-[5-(3-fluoro- 8.67 (m, 2H), 7.82 (m,phenyl)-[1,2,4]oxadiazol-3- 1H), 7.72 (m, 1H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 7.66 (m, 1H), 7.42 (m, 1H),3-yl}-pyridine 7.21 (m, 1H), 4.68 (s, 1H), 3.23 (m, 1H), 1.11 (m, 2H),0.75 (m, 2H) 691 4-[4-Cyclopropyl-5-(5-m-tolyl- 8.69 (q, 2H), 7.85 (m,[1,2,4]oxadiazol-3- 2H), 7.67 (q, 2H),ylmethylsulfanyl)-4H-[1,2,4]triazol- 7.32 (m, 2H), 4.69 (s, 2H),3-yl]-pyridine 3.2 (m, 1H), 2.35 (s, 3H), 1.11 (m, 2H), 0.76 (m, 2H) 6923-[3-(4-Cyclopropyl-5-pyridin-4-yl- 8.71 (b s, 2H), 8.36 (m,4H-[1,2,4]triazol-3- 1H), 8.28 (d, 1H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.83 (d d, 1H), 7.67 (m, 3H),5-yl]-benzonitrile 4.72 (s, 2H), 3.23 (m, 1H), 1.14 (m, 2H), 0.77 (m,2H) 693 4-{4-Cyclopropyl-5-[5-(2,5- 8.75 (t, 2H), 7.79 (m,difluoro-phenyl)-[1,2,4]oxadiazol-3- 2H), 7.26 (m, 2H),ylmethylsulfanyl]-4H-[1,2,4]triazol- 4.78 (s, 2H), 3.28 (m, 1H),3-yl}-pyridine 1.14 (m, 2H), 0.82 (m, 2H) 6944-{4-Cyclopropyl-5-[1-(5-m-tolyl- 8.67 (d d, 2H), 7.87 (m,[1,2,4]oxadiazol-3-yl)- 2H), 7.67 (d d, 2H),ethylsulfanyl]-4H-[1,2,4]triazol-3- 7.33 (m, 2H), 5.36 (q, 1H),yl}-pyridine 3.15 (m, 1H), 2.36 (s, 3H), 1.92 (d, 3H), 1.07 (m, 2H),0.72 (m, 2H) 695 4-(4-Cyclopropyl-5-{1-[5-(3- 8.69 (m, 2H), 7.6 (m,methoxy-phenyl)-[1,2,4]oxadiazol- 3H), 7.52 (m, 1H),3-yl]-ethylsulfanyl}-4H- 7.35 (t, 1H), 7.04 (d d, 1H),[1,2,4]triazol-3-yl)-pyridine 5.35 (q, 1H), 3.81 (s, 3H), 3.15 (m, 1H),1.91 (d, 3H), 1.11 (m, 2H), 0.7 (m, 2H) 696 4-{5-[5-(2-Chloro-5-methyl-8.69 (d, 2H), 7.78 (m, phenyl)-[1,2,4]oxadiazol-3- 1H), 7.67 (m, 2H),ylmethylsulfanyl]-4-cyclopropyl- 7.35 (d, 1H), 7.24 (m, 1H),4H-[1,2,4]triazol-3-yl}-pyridine 4.72 (s, 2H), 3.22 (m, 1H), 2.31 (s,3H), 1 (m, 2H), 0.76 (m, 2H) 697 2-[3-(4-Cyclopropyl-5-pyridin-4-yl-9.89 (s, 1H), 8.7 (m, 4H-[1,2,4]triazol-3- 2H), 7.68 (m, 3H),ylsulfanylmethyl)-[1,2,4]oxadiazol- 7.2 (m, 1H), 6.92 (d, 1H),5-yl]-4-methyl-phenol 4.72 (s, 2H), 3.22 (m, 1H), 2.26 (s, 3H), 1.01 (m,2H), 0.74 (m, 2H) 698 4-(5-{1-[5-(2-Chloro-5-methyl- 8.69 (d d, 2H), 7.8(q, phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.67 (m, 2H),ethylsulfanyl}-4-cyclopropyl-4H- 7.35 (d, 1H), 7.22 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.4 (q, 1H), 3.16 (m, 1H), 2.32 (s, 3H),1.93 (d, 3H), 1.09 (m, 2H), 0.73 (m, 2H)

Example 699{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenyl}-methanol

[3-(3-Chloromethyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanol (32 mg, 0.14mmol), 4-methyl-5-thiophene-3-yl-4H-[1,2,4]triazole-3-thiol (41 mg, 0.21mmol) and potassium carbonate (29 mg, 0.21 mmol) was dissolved inanhydrous acetonitrile and refluxed under nitrogen atmosphere for 1 h.The solvent was removed in vacuo and the residue was dissolved in NaHCO3(aq) and extracted with dichloromethane (′3). The organic phase wasdried (MgSO4), filtered and concentrated. The title compound wasisolated as an colorless oil (43 mg, 80%) by flash chromatography using3% methanol in dichloromethane. 1H NMR (CDCl₃), δ (ppm): 8.07 (s, 1H),7.98 (d, 1H), 7.60 (d, 1H), 7.52-7.45 (m, 3H), 7.16 (dd, 1H), 5.29 (s,2H), 4.75 (s, 2H), 4.50 (s, 2H), 3.71 (s, 1H).

The following compounds were prepared analogously to Example 699:Example No. Name 1H NMR MS 700 3-[5-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazol-3-yl]-phenol 7015-(3-Chloro-phenyl)-3-[4- 1.5 (m, 1H) 1.8 (m, 2H) 460(tetrahydro-furan-2-ylmethyl)-5- 2.0 (m, 1H) 3.7 (m,thiophen-2-yl-4H-[1,2,4]triazol-3- 1H) 3.8 (m, 1H)ylsulfanylmethyl]-[1,2,4]oxadiazole 4.1 (s, m, 3H) 4.5 (dd, 2H) 7.1 (dd,1H) 7.4 (t, 2H) 7.5 (m, 2H) 7.9 (dd, 1H) 8.0 (m, 1H 702(2-Chloro-phenyl)-{5-[5-(3-chloro- 0.8 (2d, 6H) 2.0 (m, 1H) 490phenyl)-[1,2,4]oxadiazol-3- 3.5 (dd, 1H) 3.6 (dd,ylmethylsulfanyl]-4-isobutyl-4H- 1H) 4.5 (s, 2H) 6.3 (d,[1,2,4]triazol-3-yl}-methanol 1H) 7.3 (m, 3H) 7.5 (apparent triplett,1H) 7.6 (m, 2H) 8.0 (apparent d, 1H) 8.1 (m, 1H) 7035-(2-Fluoro-5-methyl-phenyl)-3-[5- 2.4 (s, 3H) 4.6 (s, 2H) 455.9thiophen-2-yl-4-(2,2,2-trifluoro- 4.8 (q, J = 7.7 Hz, 2H)ethyl)-4H-[1,2,4]triazol-3- 7.1 (m, 1H) 7.2 (m, 1H)ylsulfanylmethyl]-[1,2,4]oxadiazole 7.4 (m, 1H) 7.5 (m, 1H) 7.6 (m, 1H)7.8 (m, 1H)

Example 7043-(2,5-Difluoro-phenyl)-5-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

5-Chloromethyl-3-(2,5-difluoro-phenyl)-[1,2,4]oxadiazole (23 mg, 0.10mmol) and 4-ethyl-5-thiophen-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione(23 mg, 0.1 mmol) was dissolved in anhydrous DMF (1 ml) and potassiumcarbonate (21 mg, 0.15 mmol) was added. After stirring for 22 h ethylacetate was added, the resulting mixture was washed twice with water andonce with brine, dried over MgSO4 and evaporated. Flash chromatographyusing heptane:ethyl acetate 1:1 yielded the title compound (20 mg, 50%).1H NMR (CDCl₃) d (ppm): 7.64 (m, 1H), 7.45 (d, 1H), 7.39 (d, 1H), 7.10(m, 3H), 4.70 (s, 2H), 4.08 (q, 2H), 1.32 (t, 3H).

The following compounds were prepared analogously to Examples 704:Example No. Name 1H NMR MS 705 5-Furan-3-yl-3-(4-methyl-5- 3.71 (s, 3H)4.51 (s, 2H) 345.92 thiophen-2-yl-4H-[1,2,4]triazol-3- 6.88 (dd, 1H)ylsulfanylmethyl)-[1,2,4]oxadiazole 7.17 (dd, 1H) 7.48 (dd, 1H) 7.51(dd, 1H) 7.54 (t, 1H) 8.18 (m, 1H) 706 3-(3-Chloro-phenyl)-5-(5-furan-2-3.78 (s, 3H) 4.64 (s, 2H) 373.96 yl-4-methyl-4H-[1,2,4]triazol-3- 6.57(dd, 1H) ylsulfanylmethyl)-[1,2,4]oxadiazole 7.09 (d, 1H) 7.38 (t, 1H)7.46 (m, 1H) 7.58 (d, 1H) 7.91 (d, 1H) 8.01 (m, 1H) 7073-(3-Chloro-phenyl)-5-(5-furan-3- 3.63 (s, 3H) 4.64 (s, 2H) 373.96yl-4-methyl-4H-[1,2,4]triazol-3- 6.85 (d, 1H) 7.39 (t,ylsulfanylmethyl)-[1,2,4]oxadiazole 1H) 7.47 (dt, 1H) 7.56 (t, 1H) 7.87(br. s, 1H) 7.91 (dt, 1H) 8.01 (t, 1H) 7085-(3-Chloro-phenyl)-3-(5-furan-2- 3.77 (s, 3H) 4.50 (s, 2H) 373.96yl-4-methyl-4H-[1,2,4]triazol-3- 6.55 (dd, 1H)ylsulfanylmethyl)-[1,2,4]oxadiazole 7.07 (d, 1H) 7.43 (t, 1H) 7.55 (m,2H) 7.95 (dt, 1H) 8.05 (t, 1H) 709 5-(3-Chloro-phenyl)-3-(5-furan-3-3.63 (s, 3H) 4.49 (s, 2H) 373.97 yl-4-methyl-4H-[1,2,4]triazol-3- 6.84(br. s, 1H) ylsulfanylmethyl)-[1,2,4]oxadiazole 7.43 (t, 1H) 7.54 (m,2H) 7.87 (s, 1H) 7.94 (d, 1H) 8.04 (m, 1H) 7104-{5-[5-(3-Chloro-phenyl)- 4.06 (s, 3H) 4.63 (s, 2H) 385.97[1,2,4]oxadiazol-3- 7.43 (t, 1H) 7.53 (m, ylmethylsulfanyl]-4-methyl-4H-1H) 7.95 (d, 1H) [1,2,4]triazol-3-yl}-pyrimidine 8.05 (t, 1H) 8.27 (dd,1H) 8.85 (d, 1H) 9.25 (d, 1H) 711 4-{5-[3-(3-Chloro-phenyl)- 4.06 (s,3H) 4.75 (s, 2H) 385.97 [1,2,4]oxadiazol-5- 7.35 (t, 1H)ylmethylsulfanyl]-4-methyl-4H- 7.42 (ddd, 1H) 7.88 (dt, 1H)[1,2,4]triazol-3-yl}-pyrimidine 7.97 (t, 1H) 8.24 (dd, 1H) 8.84 (d, 1H)9.23 (d, 1H) 712 3-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.29 (t, 3H) 4.07(q, 2H) 421.99 ethyl-5-thiophen-2-yl-4H- 4.68 (s, 2H) 7.08 (m,[1,2,4]triazol-3-ylsulfanylmethyl)- 2H) 7.35 (m, 2H) [1,2,4]oxadiazole7.44 (dd, 1H) 7.87 (dd, 1H) 713 3-(5-Chloro-2-fluoro-phenyl)-5-(4- 1.32(t, 3H) 4.18 (q, 2H) 406.02 ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.71(s, 2H) 3-ylsulfanylmethyl)- 6.51 (dd, 1H) 7.02 (dd, 1H)[1,2,4]oxadiazole 7.10 (dd, 1H) 7.37 (ddd, 1H) 7.53 (dd, 1H) 7.91 (dd,1H) 714 5-(5-Chloro-thiophen-2-yl)-3-(4- 1.30 (t, 3H) 4.09 (q, 2H)409.92 ethyl-5-thiophen-2-yl-4H- 4.47 (s, 2H) 6.96 (d,[1,2,4]triazol-3-ylsulfanylmethyl)- 1H) 7.11 (dd, 1H) [1,2,4]oxadiazole7.40 (dd, 1H) 7.47 (dd, 1H) 7.60 (d, 1H) 7155-(5-Chloro-thiophen-2-yl)-3-(4- 1.33 (t, 3H) 4.21 (q, 2H) 393.96ethyl-5-furan-2-yl-4H-[1,2,4]triazol- 4.52 (s, 2H) 3-ylsulfanylmethyl)-6.54 (dd, 1H) 6.98 (d, 1H) [1,2,4]oxadiazole 7.05 (dd, 1H) 7.55 (dd, 1H)7.62 (d, 1H) 716 5-(5-Chloro-thiophen-3-yl)-3-(4- 1.36 (t, 3H) 4.12 (q,2H) 409.92 ethyl-5-thiophen-2-yl-4H- 4.58 (s, 2H)[1,2,4]triazol-3-ylsulfanylmethyl)- 7.15 (dd, 1H) 7.43 (m, 2H)[1,2,4]oxadiazole 7.48 (dd, 1H) 7.94 (d, 1H) 7174-{5-[5-(3-Chloro-phenyl)- 1.30 (t, 3H) 4.02 (q, 2H) 443.9[1,2,4]oxadiazol-3- 4.51 (s, 2H) 5.07 (s, ylmethylsulfanyl]-4-ethyl-4H-2H) 6.72 (m, 4H) [1,2,4]triazol-3-ylmethoxy}-phenol 7.39 (t, 1H) 7.49(m, 1H) 7.89 (m, 1H) 7.99 (t, 1H) 7184-{5-[5-(5-Chloro-2-fluoro-phenyl)- 1.33 (t, 3H) 4.05 (q, 2H) 461.9[1,3,4]oxadiazol-2- 4.70 (s, 2H) 5.11 (s, ylmethylsulfanyl]-4-ethyl-4H-2H) 6.74 (m, 4H) [1,2,4]triazol-3-ylmethoxy}-phenol 7.13 (t, 1H) 7.44(m, 1H) 7.93 (dd, 1H) 719 3-(2,5-Difluoro-phenyl)-5-(4-ethyl- 7.75 (m,1H), 7.64 (d, 389.9 5-furan-2-yl-4H-[1,2,4]triazol-3- 1H), 7.23 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (d, 1H), 6.63 (dd, 1H), 4.80(s, 2H), 4.29 (q, 2H), 1.43 (t, 3H) 7203-(2,5-Difluoro-phenyl)-5-(5-furan- 8.17 (dd, 1H), 7.87 (m, 375.82-yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.74 (m, 2H),ylsulfanylmethyl)-[1,2,4]oxadiazole 7.33 (dd, 1H), 6.95 (dd, 1H), 5.01(s, 2H), 3.96 (s, 3H) 721 4-(5-{1-[3-(3-Chloro-phenyl)- 8.74 (d, 2H),7.97 (s, 1H), 400 [1,2,4]oxadiazol-5-yl]- 7.87 (m, 1H),ethylsulfanyl}-4-methyl-4H- 7.56 (d, 2H), 7.44 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 7.36 (apparent t, 1H), 5.06 (q, 1H), 3.58(s, 3H), 1.96 (d, 3H). 722 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 0.90 (m,2H), 1.22 (m, 430.1 [1,2,4]oxadiazol-3- 2H), 3.49 (m, 1H),ylmethylsulfanyl]-4-cyclopropyl- 4.81 (s, 2H), 7.26 (t, 1H),4H-[1,2,4]triazol-3-yl}-pyrimidine 7.53 (m, 1H), 8.11 (m, 2H), 8.88 (d,1H) 9.33 (s, 1H) 723 2-(5-{1-[5-(3-Chloro-phenyl)- 1.32 (t, 3H), 1.94(d, 3H), 444.1 [1,2,4]oxadiazol-3-yl]- 4.00 (s, 3H),ethylsulfanyl}-4-ethyl-4H- 4.50 (m, 2H), 5.20 (q, 1H),[1,2,4]triazol-3-yl)-5-methoxy- 7.46 (t, 1H), 7.56 (m, 1H), pyrimidine7.99 (d, 1H), 8.10 (t, 1H), 8.56 (d, 2H). 7242-(5-{1-[5-(3-Chloro-phenyl)- 1.34 (t, 3H), 1.94 (d, 3H), 414[1,2,4]oxadiazol-3-yl]- 4.50 (m, 2H), ethylsulfanyl}-4-ethyl-4H- 5.26(q, 1H), 7.36 (t, 1H), [1,2,4]triazol-3-yl)-pyrimidine 7.46 (t, 1H),7.57 (d, 1H), 7.99 (m, 1H), 8.10 (m, 1H), 8.92 (d, 2H). 7254-(5-{1-[5-(3-Chloro-phenyl)- 1.32 (t, 3H), 1.97 (d, 3H), 443.1[1,2,4]oxadiazol-3-yl]- 3.99 (s, 3H), ethylsulfanyl}-4-ethyl-4H- 4.06(m, 2H), 5.19 (q, 1H), [1,2,4]triazol-3-yl)-2-methoxy- 6.98 (bs, 1H),7.16 (m, pyridine 1H), 7.47 (t, 1H), 7.58 (m, 1H), 7.98 (dt, 1H), 8.10(m, 1H) 8.31 (d, 1H). 726 5-(5-{1-[5-(3-Chloro-phenyl)- 1.30 (t, 3H),1.96 (d, 3H), 443 [1,2,4]oxadiazol-3-yl]- 3.99 (m, 2H), 4.00 (s,ethylsulfanyl}-4-ethyl-4H- 3H), 5.16 (q, 1H),[1,2,4]triazol-3-yl)-2-methoxy- 6.87 (d, 1H), 7.47 (t, 1H), pyridine7.58 (m, 1H), 7.86 (dd, 1H), 8.00 (d, 1H), 8.11 (t, 1H) 8.40 (d, 1H).727 2-(5-{1-[5-(3-Chloro-phenyl)- 1.30 (t, 3H), 1.93 (d, 3H), 443.1[1,2,4]oxadiazol-3-yl]- 3.92 (s, 3H), ethylsulfanyl}-4-ethyl-4H- 4.52(m, 2H), 5.13 (q, 1H), [1,2,4]triazol-3-yl)-5-methoxy- 7.32 (dd, 1H),7.46 (t, 1H), pyridine 7.56 (m, 1H), 7.99 (dt, 1H), 8.10 (t, 1H), 8.25(d, 1H) 8.30 (d, 1H). 728 3-(5-{1-[5-(3-Chloro-phenyl)- 1.38 (t, 3H),1.96 (d, 3H), 444 [1,2,4]oxadiazol-3-yl]- 4.20 (s, 3H),ethylsulfanyl}-4-ethyl-4H- 4.61 (m, 2H), 5.20 (q, 1H),[1,2,4]triazol-3-yl)-6-methoxy- 7.12 (d, 1H), 7.46 (t, 1H), pyridazine7.56 (t, 1H), 8.00 (d, 1H), 8.10 (s, 1H), 8.40 (d, 1H) 7293-(5-{1-[5-(3-Chloro-phenyl)- 0.77 (m, 2H), 1.14 (m,[1,2,4]oxadiazol-3-yl]- 2H), 1.99 (d, 3H),ethylsulfanyl}-4-cyclopropyl-4H- 3.22 (m, 1H), 5.44 (q, 1H),[1,2,4]triazol-3-yl)-pyridine 7.45 (m, 2H), 7.58 (d, 1H), 8.02 (d, 1H),8.15 (m, 2H), 8.72 (d, 1H) 9.05 (s, 1H). 730 4-{5-[3-(3-Chloro-phenyl)-3.69 (s, 3H) 4.73 (s, 2H) 384.91 [1,2,4]oxadiazol-5- 7.39 (t, 1H) 7.47(m, ylmethylsulfanyl]-4-methyl-4H- 1H) 7.60 (m, 2H)[1,2,4]triazol-3-yl}-pyridine 7.92 (m, 1H) 8.02 (t, 1H) 8.79 (m, 2H)

Example 7315-(3-Chloro-phenyl)-3-(5-furan-2-yl-4-isobutyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

The title compound was synthesized according to the method described byGraybill et al. Tetrahedron lett. 2002 43, 5305-5309 fromfuran-2-carboxylic acid hydrazide (55.2 mg, 0.44 mmol),1-isothiocyanato-2-methyl-propane (47 ml, 0.38 mmol) and3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (45.0 mg, 0.20mmol) with P-BEMP (136 mg, 0.30 mmol) as base. Purification by flashchromatography (33-66% EtOAc in heptane) gave the product as an oil(12.7 mg, 15.6%). 1H NMR (CDCl₃) d (ppm): 8.08 (s, 1H), 7.97 (d, 1H),7.55 (d, 2H), 7.45 (t, 1H), 7.10 (d, 1H), 6.56 (d, 1H), 4.62 (s, 2H),4.01 (d, 2H), 2.03 (m, 1H), 0.86 (d, 6H).

General: Thiophene-2-carbohydrazide (1.5 equiv) and an isothiocyanate(1.3 equiv) were dissolved in DMF (1 ml).2-tert-Butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine(1 equiv) on polystyrene was added and the reactions were shaken on aBohdan miniblock at ambient temperature for 1 h and then for oneadditional h at 45° C. The resin was washed with dioxane:water 1:1several times. The ring closure was carried out at 85° C. for 48 h indioxane:water 1:1 on the miniblock. The resin was washed withacetonitrile (2′ 2 ml). The3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole was added to thereaction and shaken in acetonitrile at 50° C. for 2 h. The product wasfiltrated and purified on MS-directed prep-HPLC, gradient 0-100%acetonitrile over 15 min.

The following compounds were prepared analogously to Example 731:Example No. Name 1H NMR MS 732 5-(3-Chloro-phenyl)-3-[4-(3- 464.0methylsulfanyl-propyl)-5-thiophen- 2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole 7335-(3-Chloro-phenyl)-3-(4-hexyl-5- 460.0thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazole734 5-(3-Chloro-phenyl)-3-(4- 430.0 cyclopropylmethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazole 7355-(3-Chloro-phenyl)-3-[4-(3-fluoro- 484.0 benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 7365-(3-Chloro-phenyl)-3-[4-(3- 480.0 methyl-benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 7375-(3-Chloro-phenyl)-3-[4-(2- 446.0 methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 7385-(3-Chloro-phenyl)-3-[4-(3- 446.0 methyl-butyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole 7395-(3-Chloro-phenyl)-3-[4-(2-fluoro- 484.0 benzyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]- [1,2,4]oxadiazole

Example 7405-(3-Chloro-phenyl)-3-(4-ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yloxymethyl)-[1,2,4]oxadiazole

[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-methanol (28.0 mg, 0.13mmol), 4-ethyl-3-methanesulfonyl-5-thiophen-2-yl-4H-[1,2,4]triazole(35.2 mg, 0.13 mmol) and cesium carbonate (130 mg) were dissolved indimethylformamide and stirred under argon at ambient temperatures for 46h. After evaporation to dryness the crude was chromatographed on 12 gsilica, heptane/ethyl acetate 4/1 to 2/1. Collection of the appropriatefractions gave after evaporation to dryness and drying in vacuo thetitle compound (17.0 mg, 33%). 1H NMR (CDCl₃), δ (ppm): 8.13 (m, 1H),8.02 (m, 1H), 7.58 (m, 1H), 7.47 (m, 2H), 7.40 (dd, 1H), 7.14 (dd, 1H),5.74 (s, 2H), 4.04 (q, 2H), 1.38 (t, 3H).

The following compounds were prepared analogously to Example 740:Example No. Name 1H NMR MS The following compounds were preparedanalogously to Example 740: 741 4-{5-[5-(5-Chloro-2-fluoro-phenyl)- 8.92(s broad, 2 H), 8.12 388 [1,2,4]oxadiazol-3-ylmethoxy]-4- (apparent dd,1 H), 7.78 methyl-4H-[1,2,4]triazol-3-yl}- (s, 1 H), 7.56 (s broad, 2pyridine H), 7.25 (apparent t, 1 H), 5.79 (s, 2 H), 3.66 (s, 3 H). 7424-(5-{1-[5-(3-Chloro-phenyl)- 8.82 (s broad, 2 H), 384.1[1,3,4]oxadiazol-2-yl]-ethoxy}-4- 8.07-7.94 (m, 2 H), 7.69methyl-4H-[1,2,4]triazol-3-yl)- (s broad, 2 H), 7.47 (m, pyridine 2 H),6.47 (q, 1 H), 3.63 (s, 3 H), 2.02 (d, 3 H). 7434-(5-{1-[3-(3-Chloro-phenyl)- 1.92 (d, 3 H), 3.57 (s, 3 383.1isoxazol-5-yl]-ethoxy}-4-methyl- H), 6.36 (q, 1 H), 6.744H-[1,2,4]triazol-3-yl)-pyridine (s, 1 H), 7.39 (m, 2 H), 7.60 (m, 2 H),7.66 (m, 1 H), 7.78 (m, 1 H), 8.75 (m, 2 H) 7443-(5-{1-[5-(3-Chloro-phenyl)- [1,2,4]oxadiazol-3-yl]-ethoxy}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)- pyridine The following compoundswere prepared analogously to Example 740 with the exception that sodiumhydride was employed as the base and the reaction was heated at 80° C.:745 4-{5-[5-(3-Chloro-phenyl)- 8.77 (d, 2H), 8.17 (s,[1,2,4]oxadiazol-3-ylmethoxy]-4- 1H), 8.05 (d, 1H), 7.79cyclopropyl-4H-[1,2,4]triazol-3-yl}- (d, 2H), 7.62 (dd, 1H), pyridine7.52 (t, 1 H), 5.79 (s, 2H), 3.25 (m, 1H), 1.14 (d, 2H), 0.89 (m, 2H)746 4-{5-[5-(3-Chloro-phenyl)-isoxazol- 8.77 (d, 2H), 7.79 (m,3-ylmethoxy]-4-cyclopropyl-4H- 3H), 7.7 (m, 1H), 7.44[1,2,4]triazol-3-yl}-pyridine (m, 2H), 6.84 (s, 1H), 5.71 (s, 2H), 3.21(m, 1H), 1.13 (d, 2H), 0.82 (m, 2H)

The following compounds were prepared analogously to Example 740 withthe exception that sodium hydride was employed as the base and thereaction was heated at 80° C.:

Example 7475-(2-Methoxy-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

HBTU (171 mg, 0.45 mmol) and HOBT (8 mg, 0.06 mmol) were added to asolution of 2-methoxy benzoic acid (68 mg, 0.45 mmol) and DIPEA (192 ml,1.11 mmol) in DMF (3 ml). After 10 minN-hydroxy-2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-acetamidine(100 mg, 0.37 mmol) was added. The reaction mixture was stirred at RTfor 7 h and then at 110° C. over night. After cooling the reactionmixture was diluted with water and extracted with CH₂Cl₂. The organicphase was dried and concentrated. Flash chromatography (heptane/EtOAc1:2) afforded 1.9 mg (11%) of the desired product.

1H NMR (CDCl₃), d (ppm): 7.99 (m, 1H), 7.53 (m, 1H), 7.50 (m, 1H), 7.47(m, 1H), 7.16 (m, 1H), 7.04 (m, 2H), 4.52 (s, 2H), 3.94 (s, 3H), 3.71(s, 3H).

The following compounds were prepared analogously to Example 747:Example No. Name 1H NMR MS 748 5-Furan-2-yl-3-(4-methyl-5- 3.72 (s, 3H)4.52 (s, 2H) 345.92 thiophen-2-yl-4H-[1,2,4]triazol-3- 6.61 (dd, 1H)ylsulfanylmethyl)-[1,2,4]oxadiazole 7.16 (dd, 1H) 7.30 (dd, 1H) 7.47(dd, 1H) 7.50 (dd, 1H) 7.67 (dd, 1H) 7493-[3-(4-Methyl-5-thiophen-2-yl-4H- 414.0[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazol-5-yl]-benzoic acidmethyl ester 750 5-(2-Fluoro-phenyl)-3-(4-methyl-5- 374.0thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazole751 5-(2,5-Difluoro-phenyl)-3-(4- 392.0 methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 7523-(4-Methyl-5-thiophen-2-yl-4H- 382.1[1,2,4]triazol-3-ylsulfanylmethyl)-5- (3-vinyl-phenyl)-[1,2,4]oxadiazole753 5-(3-Difluoromethoxy-phenyl)-3-(4- 422.0 methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 7545-(4-Methoxy-thiophen-3-yl)-3-(4- 392.0 methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)- [1,2,4]oxadiazole 7555-(2-Chloro-phenyl)-3-(4-methyl-5- 390.0thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazole756 5-(4-Fluoro-phenyl)-3-(4-methyl-5- 374.0thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazole

Example 7573-(3-Chloro-phenyl)-5-[1-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-ethyl]-[1,2,4]oxadiazole

DMF was added to a mixture of2-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionicacid (50 mg, 0.186 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDCI) (35.7 mg, 0.186 mmol), 1-hydroxybenzotriazolehydrate (HOBT) (28.5 mg, 0.186 mmol) and 3-chloro-N-hydroxy-benzamidine(29.3 mg, 0.172 mmol) at room temperature and stirred overnight. Thereaction mixture was diluted with ethyl acetate (75 ml), washed withwater 3 times, once with 1.0 M HCl (30 ml), saturated NaHCO₃ (30 ml) andsaturated brine (30 ml), dried over anhydrous sodium sulfate, filteredand concentrated in vacuo. DMF (1 ml) was added to the residue and theresulting solution was heated at 135° C. for 3 h to effect cyclizationto oxadiazole. After cooling the reaction mixture was diluted with ethylacetate (75 ml), washed with water 3 times, once with 1.0 M HCl (30 ml),saturated NaHCO₃ (30 ml) and saturated brine (30 ml), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. The titlecompound (46.5 mg, 66.9%) was purified by SPE chromatography on silicagel using 50 ml 40%, 150 ml 50% ethyl acetate in hexanes. 1H NMR(CDCl₃), δ (ppm): 8.03 (s, 1H), 7.92 (m, 1H), 7.47 (m, 4H), 7.18 (dd,1H), 4.99 (q, 1H), 3.64 (s, 3H), 1.97 (d, 3H).

The following compounds were prepared analogously to Example 757: Exam-ple No. Name 1H NMR MS 758 3-(5-{1-[3-(3-Chloro-phenyl)- 8.88 (d, 1H),8.76 (dd, [1,2,4]oxadiazol-5-yl]- 1H), 8.03 (m, 2H),ethylsulfanyl}-4-methyl-4H- 7.93 (d, 1H), 7.74 (m,[1,2,4]triazol-3-yl)-pyridine 3H), 5.09 (m, 1H), 3.58 (s, 3H), 2.00 (d,3H)

The following compounds were prepared analogously to Example 10: ExampleNo. Name 759 5-(1-Chloro-ethyl)-3-(3-chloro-phenyl)- [1,2,4]oxadiazole3-(1-Chloro-ethyl)-5-m-tolyl-[1,2,4]oxadiazole 7613-(1-Chloro-ethyl)-5-(3-methoxy-phenyl)- [1,2,4]oxadiazole 7623-(1-Chloro-ethyl)-5-(2-chloro-5-methyl-phenyl)- [1,2,4]oxadiazole 7633-(1-Chloro-ethyl)-5-(2,5-difluoro-phenyl)- [1,2,4]oxadiazole 7643-(1-Chloro-ethyl)-5-(2-fluoro-5-methyl-phenyl)- [1,2,4]oxadiazole 7653-[3-(1-Chloro-ethyl)-[1,2,4]oxadiazol-5-yl]- benzonitrile

The following compounds were prepared analogously to Example 40: ExampleNo. Name 1H NMR MS 766 4-(5-{1-[5-(2-Chloro-5-methyl- 8.74 (d, 2H), 7.79(s, phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.57 (d d, 2H),ethylsulfanyl}-4-methyl-4H- 7.38 (d, 1H), 7.25 (d,[1,2,4]triazol-3-yl)-pyridine 1H), 5 (q, 1H), 3.62 (s, 3H), 2.33 (s,3H), 1.92 (d, 3H) 767 4-(5-{1-[5-(2,5-Difluoro-phenyl)- 8.67 (d, 2H),7.7 (m, [1,2,4]oxadiazol-3-yl]- 1H), 7.57 (d d, 2H),ethylsulfanyl}-4-methyl-4H- 7.2 (m, 2H), 5 (q, 1H),[1,2,4]triazol-3-yl)-pyridine 3.61 (s, 3H), 1.87 (d, 3H) 7684-(5-{1-[5-(2-Fluoro-5-methyl- 8.77 (d, 2H), 7.85 (m,phenyl)-[1,2,4]oxadiazol-3-yl]- 1H), 7.61 (m, 2H),ethylsulfanyl}-4-methyl-4H- 7.38 (m, 1H), 7.06 (t, 1H),[1,2,4]triazol-3-yl)-pyridine 5.02 (q, 1H), 3.66 (s, 3H), 2.37 (s, 3H),1.94 (d, 3H) 769 4-(4-Cyclopropyl-5-{1-[5-(2-fluoro- 8.75 (d, 2H), 7.9(m, 5-methyl-phenyl)-[1,2,4]oxadiazol- 1H), 7.74 (m, 2H),3-yl]-ethylsulfanyl}-4H- 7.38 (m, 1H), 7.13 (m, 1H),[1,2,4]triazol-3-yl)-pyridine 5.45 (q, 1H), 3.24 (m, 1H), 2.39 (s, 3H),2 (d, 3H), 1.15 (m, 2H), 0.79 (m, 2H) 7703-{3-[1-(4-Methyl-5-pyridin-4-yl- 8.76 (d d, 2H), 8.4 (s,4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 8.32 (d, 1H),ethyl]-[1,2,4]oxadiazol-5-yl}- 7.87 (d, 1H), 7.65 (t, 1H), benzonitrile7.59 (m, 2H), 5.07 (q, 1H), 3.67 (s, 3H), 2.59 (s, 2H), 1.91 (d, 3H) 7713-{3-[1-(4-Cyclopropyl-5-pyridin- 8.77 (m, 2H), 8.42 (d,4-yl-4H-[1,2,4]triazol-3-ylsulfanyl)- 1H), 8.38 (m, 1H),ethyl]-[1,2,4]oxadiazol-5-yl}- 7.9 (m, 1H), 7.71 (m, 3H), benzonitrile5.49 (q, 1H), 3.25 (m, 1H), 2 (d, 3H), 1.17 (m, 2H), 0.81 (m, 2H) 7723-{1-[5-(3-Chloro-phenyl)- 8.77 (br s, 2H), 8.18 (d,[1,3,4]oxadiazol-2-yl]- 2H), 7.98 (s, 1H),ethylsulfanyl}-5-pyridin-4-yl- 7.87 (d, 1H), 7.52 (d, 1H),[1,2,4]triazol-4-ylamine 7.44 (t, 1H), 5.66 (s, 2H), 4.88 (q, 1H), 1.98(d, 3H)

The following compounds were prepared analogously to Example 316:Example No. Name 7733-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-methyl- propionic acidhydrazide 774 Rac-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyricacid hydrazide

The following compounds were prepared analogously to Example 318:Example No. Name 775 2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-cyclopropanecarboxylic acid hydrazide

Example 7763-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionicacid hydrazide

3,3-Dimethyl-dihydro-furan-2,5-dione (6.4 g) was heated at 50° C. inethanol (150 mL) overnight. The solvent was removed in vacuo and theresidue triturated with hexane to yield 2,2-Dimethyl-succinic acid4-ethyl ester (4.66 g) which was used without further purification.t-Butanol (7.5 mL) was added to a mixture of 2,2-Dimethyl-succinic acid4-ethyl ester (2.74 g, 15.7 mmol) in dichloromethane (62 mL) containingmagnesium sulfate (7.5 g) and conc. sulfuric acid (0.85 mL) and themixture was stirred at room temperature overnight. Saturated sodiumbicarbonate solution was added and the product was extracted intodichloromethane, washed with brine solution, dried and concentrated toyield the diested as a colorless oil (1.89 g). The ethyl ester washydrolyzed by trating the crude sample with potassium hydroxide (2.75 g)in a mixture of ethanol (50 mL) and water (25 mL) at room temperaturefor 2 h. The reaction was acidified using 1N HCl (aq) and extracted intoether, dried and concentrated to yield 2,2-Dimethyl-succinic acid1-tert-butyl ester (1.4 g). This acid was treated under the conditionsof Example 320 (step 1) to yield3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionicacid tert-butyl ester (1.9 g). This t-Bu ester was deprotected usingformic acid (19 mL) at 50° C. for 20 min. The crude product wasconcentrated and triturated with a mixture of ether and hexane to yield3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionicacid (1.12 g). To a solution of3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2,2-dimethyl-propionicacid (561 mg, 2 mmol) and triethylamine (1.1 mL, 8 mmol) in THF (9 ml),isobutyl chloroformate (0.31 mL, 2.4 mmol) was added dropwise at −78° C.After being stirred for 1 h, hydrazine hydrate (1 mL, 11 mmol) wasadded. The reaction mixture was stirred at room temperature for 1 h andconcentrated. A small amount of ice was added to quence any excessreagent and precipitate the product, which was collected by filtrationto give 482 mg of the title compound.

The following compounds were prepared analogously to Example 320:Example No. Name 777(S)-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-hydrazinocarbonyl-ethyl}-carbamic acid tert-butyl ester

Example 7783-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole

Step 1: 3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid(ethoxy-thiophen-2-yl-methylene)-hydrazide:3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid hydrazide(266.69 mg, 1 mmol) was mixed with thiophene-2-carboximidic acid ethylester (191.6 mg, 1 mmol) in ethanol (6 ml) and stirred at roomtemperature overnight. The reaction was quenched with water, extractedwith ethyl acetate, dried and concentrated in vacuo. The crude productwas triturated with hexane to yield3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid(ethoxy-thiophen-2-yl-methylene)-hydrazide as a white solid (305 mg,75%). 1H-NMR (CDCl₃) d (ppm): 8.99 (ws, 1H), 8.09 (s, 1H), 7.98 (d, 1H),7.41 (m, 4H), 7.08 (dd, 1H), 4.27 (q, 2H), 3.34 (m, 4H) and 1.41 (t,3H). Step 2:3-(3-Chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole:3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionic acid(ethoxy-thiophen-2-yl-methylene)-hydrazide (81 mg, 0.2 mmol) was mixedwith 2M methylamine (0.3 ml in THF) in ethanol (2 ml) at 70˜80° C.overnight. The reaction mixture was concentrated with silica gel andpurified by column chromatography with 0.5˜2.0% methanol in ethylacetate to give 54 mg (72.5%) of3-(3-chloro-phenyl)-5-[2-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]oxadiazole.1H-NMR (CDCl₃) d (ppm): 8.08 (s, 1H), 7.97 (d, 1H), 7.41 (m, 4H), 7.20(dd, 1H), 3.80 (s, 3H), 3.68 (dd, 2H), 3.38 (dd, 2H).

The following compounds were prepared analogously to Example 778:Example No. Name 1H NMR MS 779 3-(3-Chloro-phenyl)-5-[2-(4-ethyl- 8.08(s, 1H), 7.97 (d, 5-thiophen-2-yl-4H-[1,2,4]triazol-3- 1H), 7.47 (m,4H), yl)-ethyl]-[1,2,4]oxadiazole 7.20 (dd, 1H), 4.20 (q, 2H), 3.72 (dd,2H), 3.38 (dd, 2H) and 1.47 (t, 3H) 7805-(3-Chloro-phenyl)-3-(5-furan-2- 8.11 (s, 1H), 8.01 (d,yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.61 (s, 1H),ylmethyl)-[1,2,4]oxadiazole 7.58 (d, 1H), 7.48 (t, 1H), 7.11 (d, 1H),6.59 (m, 1H), 4.48 (s, 2H) and 3.92 (s, 3H) 7812-(3-Chloro-phenyl)-5-[2-(5-furan- 8.04 (s, 1H), 7.93 (d,2-yl-4-methyl-4H-[1,2,4]triazol-3- 1H), 7.60 (s, 1H),yl)-ethyl]-[1,3,4]oxadiazole 7.52 (d, 1H), 7.46 (t, 1H), 7.06 (d, 1H),6.59 (m, 1H), 3.87 (s, 3H), 3.65 (t, 2H) and 3.38 (t, 2H) 7822-(3-Chloro-phenyl)-5-[2-(4-ethyl- 8.05 (s, 1H), 7.94 (d,5-furan-2-yl-4H-[1,2,4]triazol-3-yl)- 1H), 7.60 (s, 1H),ethyl]-[1,3,4]oxadiazole 7.52 (d, 1H), 7.47 (t, 1H), 7.10 (d, 1H), 6.59(m, 1H), 4.30 (q, 2H), 3.67 (t, 2H), 3.39 (t, 2H) and 1.43 (t, 3H) 7832-(3-Chloro-phenyl)-5-[2-(4- 8.05 (s, 1H), 7.94 (d, 383.12cyclopropyl-5-furan-2-yl-4H- 1H), 7.63 (s, 1H),[1,2,4]triazol-3-yl)-ethyl]- 7.52 (d, 1H), 7.46 (t, 1H),[1,3,4]oxadiazole 7.01 (d, 1H), 6.58 (m, 1H), 3.67 (dd, 2H), 3.51 (t,2H), 3.33 (m, 1H) 1.25 (m, 2H) and 0.93 (m, 2H)

Example 7844-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

Step 1: Isonicotinic acid{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydrazide:3-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propionimidic acid ethylester hydrochloride (473.3, 1.5 mmol) was mixed with isonicotinic acidhydrazide (205.7 mg, 1.5 mmol) in ethanol (8 ml) at 60° C. for an h andthen at room temperature for 2 h. The reaction mixture was diluted withdichloromethane and washed with water. The organic layer was dried,concentrated with vacuum and the residue was triturated with ether togive 490 mg (78.9%) of isonicotinic acid{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydrazideas white solid.

Step 2:4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine(47.1 mg, 82%) as white solid was obtained from isonicotinic acid{4-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-1-ethoxy-butylidene}-hydrazide(60 mg, 0.15 mmol) reacted with 2M methylamine (0.45 ml, 0.9 mmol) inethanol (1 ml) at 60° C. overnight. 1H-NMR (CDCl₃) d (ppm): 8.77 (d,2H), 8.02 (s, 1H), 7.91 (d, 1H), 7.58 (d, 2H), 7.42 (m, 2H), 3.76 (s,3H), 3.66 (t, 2H) and 3.38 (t, 2H).

The following compounds were prepared analogously to Example 784: Exam-ple No. Name 1H NMR MS 785 4-(5-{2-[3-(3-Chloro-phenyl)- 8.79 (d, 2H),8.05 (s, [1,2,4]oxadiazol-5-yl]-ethyl}-4- 1H), 7.94 (d, 1H),ethyl-4H-[1,2,4]triazol-3-yl)- 7.58 (d, 2H), 7.43 (m, pyridine 2H), 4.16(q, 2H), 3.72 (t, 2H), 3.40 (t, 2H) and 1.44 (t, 3H) 7864-(5-{2-[3-(3-Chloro-phenyl)- 8.77 (d, 2H), 8.05 (s,[1,2,4]oxadiazol-5-yl]-ethyl}-4- 1H), 7.93 (d, 1H),cyclopropyl-4H-[1,2,4]triazol- 7.73 (d, 2H), 7.44 (m, 3-yl)-pyridine2H), 3.72 (t, 3H), 3.51 (t, 2H), 3.38 (m, 1H), 1.23 (m, 2H) and 0.79 (m,2H)

4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine

Step 1: N-Cyclopropyl-isonicotinamide: Isonicotinic acid ethyl ester(3.0 g, 20 mmol) was mixed with cyclopropylamine (2 ml) at 120° C. in asealed vial for 40 h. The reaction mixture was triturated with ether togive 1.62 g (50%) of N-cyclopropyl-isonicotinamide as off-white solid.1H-NMR (CDCl₃) d (ppm): 8.73 (d, 2H), 7.60 (d, 2H) and 6.55 (w, 1H),2.92 (m, 1H), 0.90 (m, 2H) and 0.66 (m, 2H). Step 2:N-Cyclopropyl-isonicotinimidoyl chloride hydrochloride:N-Cyclopropyl-isonicotinamide (1.62 g, 10 mmol) was reacted with SOCl2(12 g, 100 mol) at 80° C. overnight. The reaction mixture wasconcentrated and triturated with dichloromethane to give 1.3 g (64%) ofN-cyclopropyl-isonicotinimidoyl chloride hydrochloride as yellow solid.Step 3:4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine:(R)-3-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-butyric acid hydrazide(56 mg, 0.2 mmol) was mixed with N-cyclopropyl-isonicotinimidoylchloride hydrochloride (40.6 mg, 0.2 mmol) and K₂CO₃ (60 mg, 0.43 mmol)in DMF (1 ml) at 100° C. for 3 h. The reaction mixture was dilute withdichloromethane and then washed with water. The organic layer wasconcentrated and purified with 5˜6% methanol in ethyl acetate to give 32mg (39%) of the title compound. 1H-NMR (CDCl₃) d (ppm): 8.78 (d, 2H),8.05 (s, 1H), 7.96 (d, 1H), 7.73 (d, 2H), 7.45 (m, 2H), 4.15 (q, 1H),3.64 (dd, 1H), 3.31 (m, 2H), 1.68 (d, 3H), 1.25 (m, 2H) and 0.79 (m,2H).

The following compounds were prepared analogously to Example 787: Itshould be noted that some reactions provided 1,3,4-oxadiazolecyclization products with loss of the methylamino or cyclopropylaminogroup instead of or as well as the triazole product. Example No. Name 1HNMR MS 788 4-(5-{2-[3-(3-Chloro-phenyl)- 8.74 (d, 2H), 8.04 (s,[1,2,4]oxadiazol-5-yl]-2-methyl- 1H), 7.94 (d, 1H),propyl}-4-cyclopropyl-4H- 7.67 (d, 2H), 7.43 (m, 2H),[1,2,4]triazol-3-yl)-pyridine 3.48 (s, 2H), 3.09 (m, 1H), 1.75 (s, 6H),1.16 (m, 2H) and 0.68 (m, 2H) 789 4-(5-{2-[5-(3-Chloro-phenyl)- 8.76 (w,2H), 8.03 (s, [1,3,4]oxadiazol-2-yl]-propyl}-4- 1H), 7.92 (d, 1H),cyclopropyl-4H-[1,2,4]triazol-3-yl)- 7.72 (d, 2H), 7.44 (m, pyridine2H), 4.13 (m, 1H), 3.72 (dd, 1H), 3.43 (m, 1H), 3.27 (dd, 1H), 1.66 (d,3H), 1.25 (m, 2H) and 0.79 (m, 2H) 790 4-(5-{2-[3-(3-Chloro-phenyl)-8.78 (d, 2H), 8.01 (s, [1,2,4]oxadiazol-5-yl]-1-methyl- 1H), 7.91 (d,1H), ethyl}-4-cyclopropyl-4H- 7.73 (d, 2H), 7.49 (d, 1H),[1,2,4]triazol-3-yl)-pyridine 7.42 (t, 1H), 3.99 (m, 1H), 3.83 (dd, 1H),3.48 (m, 1H), 3.39 (m, 1H), 1.61 (d, 3H), 1.25 (m, 2H), 0.98 (m, 1H),0.74 (m, 1H) 791 cis-4-(5-{2-[3-(3-Chloro-phenyl)- 8.73 (d, 2H), 7.88(s, [1,2,4]oxadiazol-5-yl]- 1H), 7.78 (d, 1H),cyclopropyl}-4-cyclopropyl-4H- 7.65 (d, 2H), 7.41 (d, 1H),[1,2,4]triazol-3-yl)-pyridine 7.34 (t, 1H), 3.20 (m, 1H), 2.89 (m, 2H),2.54 (dd, 1H), 2.00 (td, 1H), 1.20 (m, 2H), 0.83 (m, 2H) 7924-(5-{2-[3-(3-Chloro-phenyl)- 8.82 (m, 2H), 7.98 (s,[1,2,4]oxadiazol-5-yl]-1,1-dimethyl- 1H), 7.90 (m, 3H),ethyl}-[1,3,4]oxadiazol-2-yl)- 7.47 (d, 1H), 7.39 (t, 1H), pyridine 3.51(s, 2H), 1.70 (s, 6H) 793 4-(5-{2-[3-(3-Chloro-phenyl)- 8.76 (d, 2H),8.07 (s, [1,2,4]oxadiazol-5-yl]-2-methyl- 1H), 7.97 (d, 1H),propyl}-[1,3,4]oxadiazol-2-yl)- 7.77 (d, 2H), 7.49 (dd, 1H), pyridine7.43 (t, 1H), 3.53 (s, 2H), 1.69 (s, 6H) 7944-(5-{2-[3-(3-Chloro-phenyl)- 8.82 (d, 2H), 8.05 (m,[1,2,4]oxadiazol-5-yl]-1-methyl- 1H), 7.95 (d, 1H),ethyl}-[1,3,4]oxadiazol-2-yl)- 7.91 (d, 2H), 7.50 (dd, 1H), pyridine7.42 (t, 1H), 3.94 (dd, 1H), 3.67 (dd, 1H), 3.41 (dd, 1H), 1.66 (d, 3H)795 4-(5-{2-[3-(3-Chloro-phenyl)- 8.77 (d, 2H), 7.81 (m,[1,2,4]oxadiazol-5-yl]- 4H), 7.42 (d, 1H),cyclopropyl}-[1,3,4]oxadiazol-2- 7.32 (t, 1H), 3.07 (q, 1H),yl)-pyridine 2.99 (q, 1H), 2.41 (q, 1H), 2.08 (td, 1H) 7964-(5-{2-[3-(3-Chloro-phenyl)- 8.76 (d, 2H), 7.85 (m,[1,2,4]oxadiazol-5-yl]- 1H), 7.77 (d, 1H), cyclopropyl}-4-methyl-4H-7.55 (d, 2H), 7.44 (dd, 1H), [1,2,4]triazol-3-yl)-pyridine 7.34 (t, 1H),3.70 (s, 3H), 2.89 (m, 1H), 2.72 (m, 1H), 2.51 (q, 1H), 2.02 (dt, 1H)797 4-(5-{2-[5-(3-Chloro-phenyl)- 8.79 (d, 2H), 8.02 (s,[1,3,4]oxadiazol-2-yl]-propyl}-4- 1H), 7.93 (d, 1H),methyl-4H-[1,2,4]triazol-3-yl)- 7.59 (d, 2H), 7.53 (d, 1H), pyridine7.46 (t, 1H), 4.03 (m, 1H), 3.80 (s, 3H), 3.52 (m, 1H), 3.23 (dd, 1H),1.66 (d, 3H) 798 4-(5-{2-[3-(3-Chloro-phenyl)- 8.81 (d, 2H), 8.07 (s,[1,2,4]oxadiazol-5-yl]-propyl}- 1H), 7.97 (d, 1H),[1,3,4]oxadiazol-2-yl)-pyridine 7.87 (d, 2H), 7.50 (d, 1H), 7.43 (t,1H), 3.91 (q, 1H), 3.66 (dd, 1H), 3.44 (dd, 1H), 1.65 (d, 3H) 7994-(5-{2-[3-(3-Chloro-phenyl)- 8.80 (d, 2H), 8.05 (s,[1,2,4]oxadiazol-5-yl]-propyl}-4- 1H), 7.95 (d, 1H),methyl-4H-[1,2,4]triazol-3-yl)- 7.61 (d, 2H), 7.51 (d, 1H), pyridine7.45 (t, 1H), 4.07 (q, 1H), 3.75 (s, 3H), 3.48 (dd, 1H), 3.23 (dd, 1H),1.68 (d, 3H) 800 4-(5-{2-[3-(3-Chloro-phenyl)- 8.78 (d, 2H), 8.05 (s,[1,2,4]oxadiazol-5-yl]-propyl}-4- 1H), 7.96 (d, 1H),cyclopropyl-4H-[1,2,4]triazol-3-yl)- 7.74 (d, 2H), 7.50 (dd, 1H),pyridine 7.46 (t, 1H), 4.15 (q, 1H), 3.64 (dd, 1H), 3.31 (m, 2H), 1.67(d, 3H), 1.25 (m, 2H), 0.81 (m, 2H) 801 (S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4- cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamic acid tert-butyl ester

Example 802(S)—1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine

(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-carbamicacid tert-butyl ester (135 mg) was mixed with 96% formic acid (1.3 mL)and heated at 50° C. for 1 h. The reaction mixture was concentrated invacuo. The residue was quenched with saturated sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried with sodiumsulfate and concentrated. Purification was performed by flash columnsilica gel chromatography with 2-3% (2 M ammonia methanol) indichloromethane to give 106 mg of the title compound as an off-whitesolid. 1H NMR (CDCl₃): d ppm 8.73 (d, 2H), 8.03 (s, 1H), 7.93 (d, 1H),7.69 (d, 2H), 7.46 (d, 1H), 7.42 (t, 1H), 5.02 (dd, 1H), 3.61 (dd, 1H),3.49 (dd, 1H), 3.35 (m, 1H), 2.47 (br s, 2H), 1.20 (m, 2H), 0.75 (m, 2H)

Example 803(S)-[1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethyl]-dimethyl-amine

Sodium cyanoborohydride (0.1 mL, 1M in THF) was added to a solution of(S)-1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-2-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-ethylamine(30 mg) in methanol (0.8 mL) containing 96% formic acid (0.1 mL) and 37%formalin solution (0.1 mL). The residue was quenched with water andextracted with ethyl acetate. The organic layer was dried with sodiumsulfate and concentrated. Purification was performed by flash columnsilica gel chromatography with 3% (2 M ammonia methanol) indichloromethane to give 22 mg of the title compound.

1H NMR (CDCl₃): d ppm 8.76 (d, 2H), 8.06 (s, 1H), 7.97 (d, 1H), 7.73 (d,2H), 7.47 (d, 1H), 7.45 (t, 1H), 5.00 (dd, 1H), 3.76 (dd, 1H), 3.51 (dd,1H), 3.42 (m, 1H), 2.45 (br s, 6H), 1.26 (m, 2H), 0.88 (m, 1H), 0.79 (m,1H)

Example 8048-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine

37 mg (0.25 mmol) Me3OBF4 was added to a solution of 60 mg (0.21 mmol)3-[5-(3-chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidin-2-one in 2ml CH₂Cl₂. The mixture was stirred overnight at room temperature. Thereaction mixture was diluted with CH₂Cl₂, washed with NaHCO3 (sat),dried and concentrated. The residue was dissolved in 3 ml EtOH and 22 mg(0.16 mmol) isonicotinic hydrazide was added. The solution was heatedwith microwaves at 120° C. for 10 min. The reaction mixture was cooledand the volatiles were removed under reduced pressure. The crude productwas purified by preparative HPLC to afford 17 mg (20%) of the desiredproduct. 1H NMR (CDCl₃): d ppm 1.75 (m, 1H) 1.99 (m, 1H) 2.21 (m, 2H)3.16 (dd, 1H) 3.73 (m, 1H) 3.85 (dd, 1H) 4.07 (m, 1H) 4.19 (m, 1H) 7.47(t, 1H) 7.56 (m, 1H) 7.67 (m, 2H) 8.01 (m, 1H) 8.11 m, 1H) 8.76 (d, 2H).

The following compounds were prepared analogously to Example 804: Exam-ple No. Name 1H NMR MS 805 8-[5-(3-Chloro- 1.69 (m, 1H) 1.99 (m, 1H)phenyl)-[1,2,4]oxadiazol-3- 2.18 (m, 2H) ylmethyl]-3-thiophen-2-yl- 3.11(m, 1H) 3.67 (m, 1H) 5,6,7,8-tetrahydro- 3.87 (m, 1H) 4.02 (m, 1H)[1,2,4]triazolo[4,3- 4.24 (m, 1H) a]pyridine 7.15 (m, 1H) 7.47 (m, 3H)7.56 (m, 1H) 8.01 (d, J = 7.83 Hz, 1H) 8.12 (d, J = 1.77 Hz, 1H) 8068-[5-(5-Chloro-2-fluoro- 1.76 (m, 1H) 2.00 (m, 1H)phenyl)-[1,2,4]oxadiazol-3- 2.21 (m, 2H) ylmethyl]-3-pyridin-4-yl- 3.22(dd,, 1H) 3.74 (m, 1H) 5,6,7,8-tetrahydro- 3.87 (dd, 1H) 4.09 (m,[1,2,4]triazolo[4,3- 1H) 4.19 (m, 1H) a]pyridine 7.23 (m, 1H) 7.53 (m,1H) 7.68 (m, 2H) 8.10 (dd, 1H) 8.77 (m, 2H)

Example 8075-(5-Bromo-4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-3-(3-chloro-phenyl)-[1,2,4]oxadiazole

3-(3-Chloro-phenyl)-5-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazolewas mixed with 30 ml of chloroform/pyridine (25/1) at room temperature.Then bromine in chloroform (0.5 ml) was added dropwise and the reactionmixture was heated at 70° C. overnight. The reaction mixture was dilutedwith chloroform and washed with saturated NH₄Cl twice and the organiclayer was dried with sodium sulfate, concentrated, the residue wastriturated with diethyl ether to give the title compound (1.5 g, 57.5%,yellow solid). 1H-NMR (CDCl₃) d (ppm): 8.05 (s, 1H), 7.94 (d, 1H), 7.47(d, 1H), 7.43 (t, 1H), 4.66 (s, 2H) and 3.59 (s, 3H).

Example 8083-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenylamine

To{3-[3-(4-Methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)[1,2,4]oxadiazole5-yl-phenyl}-carbamic acid tert-butyl ester (88.0 mg, 0.19 mmol) indichloromethane (3 ml) at 0° C. added TFA (1.5 ml) and allowed to stirfor 1 h. The reaction mixture was warmed to room temperature and thesolvent was removed under vacuum. Dichloromethane was added to theresulting residue and the mixture was cooled to 0° C. and saturatedsodium bicarbonate was added to the stirring solution until turningbasic (pH˜8). The mixture was then transferred to a separatory funneland the product was extracted with dichloromethane, dried usinganhydrous sodium sulfate, and concentrated in vacuo. The resultingresidue was titurated with ether and 61.1 mg (87%) of3-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-phenylaminewas isolated (light yellow solid). 1H NMR (DMSO-d6) d (ppm): 7.81 (d,1H), 7.64 (d, 1H), 7.23 (m, 4H), 6.84 (d, 1H), 5.57 (s, 2H), 4.50 (s,2H), 3.72 (s, 3H).

The following compounds were prepared analogously to Example 98: ExampleNo. Name 1H NMR MS 809 5-(3-Chloro-phenyl)-3-(4-methyl-5- 423.01thiophen-2-yl-4H-[1,2,4]triazole-3- sulfonylmethyl)-[1,2,4]oxadiazole810 5-(3-Chloro-phenyl)-3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazole-3- sulfinylmethyl)-[1,2,4]oxadiazole

The following compounds were prepared analogously to Example 93: ExampleNo. Name 1H NMR MS 811 2-Methyl-6-[3-(4-methyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3- ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-pyridine

Example 8124-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-pyridin-2-ol

HBr (1 ml) and HOAc (1 ml) were added to4-(5-{1-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-ethylsulfanyl}-4-ethyl-4H-[1,2,4]triazol-3-yl)-2-methoxy-pyridine(9 mg, 0.02 mmol) and the reaction was stirred at 80° C. on. SaturatedNaHCO₃ (aq) was added to the reaction and the mixture was extractedthree times with dichloromethane. The combined organic phases were driedand concentrated to give the title compound (8.5 mg, 99%). 1H NMR(CDCl₃), δ (ppm): 1.37 (t, 3H), 1.96 (d, 3H), 4.10 (q, 2H), 5.23 (q,1H), 6.80 (m, 2H), 7.49 (t, 2H), 7.59 (m, 1H), 7.99 (d, 1H), 8.11 (s,1H).

Example 8134-(5-{2-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-yl]-propyl}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

84 microl (0.21 mmol, 2.5 M) n-BuLi was added dropwise to a solution of37 mg (0.21 mmol) 4-(4,5-dimethyl-4H-[1,2,4]triazol-3-yl)-pyridine in2.1 ml THF at 0° C. After 20 min a solution of 60 mg (0.21 mmol)3-(1-bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole was addeddropwise. The reaction mixture was allowed to reach room temperature andstirred over night. NH₄Cl(sat) was added and the mixture was extractedtwice with EtOAc. The organic phase was dried and concentrated.Flashchromatography (CH₂Cl₂/MeOH 20:1) afforded 7.7 mg (10%) of thedesired product. 1H NMR (CDCl₃), d (ppm): 1.57 (d, 3H) 3.16 (m, 1H) 3.38(m, 1H) 3.71 (s, 3H) 3.84 (d, 1H) 7.46 (t, 1H) 7.55 (m, 1H) 7.58 (m, 2H)7.98 (m, 1H) 8.10 (t, 1H) 8.77 (d, 2H)

Example 814[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine

10 mg (0.4 mmol) NaH was added to a solution of 38 mg (0.2 mmol)methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine in 3 mlDMF under an atmosphere of nitrogen. After 10 min a solution of 50 mg(0.22 mmol) 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole in 2 mlDMF was added. After stirring for 45 min NH₄Cl(sat) was added and themixture was extracted twice with CHCl₃. The organic phase was dried andconcentrated. Flashchromatography (CH₂Cl₂/MeOH 20:1) afforded 41 mg(54%) of the desired product. 1H NMR (CDCl₃), d (ppm): 3.07 (s, 3H) 3.71(s, 3H) 4.56 (s, 2H) 7.45 (m, 1H) 7.55 (m, 1H) 7.62 (d, 2H) 7.98 (d, 1H)8.09 (m, 1H) 8.73 (d, 2H).

Example 8158-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine

32 mg (1.31 mmol) NaH was added to a solution of 193 mg (0.96 mmol)3-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine in 10ml DMF at room temperature. After 10 min 200 mg (0.87 mmol)5-(3-chloro-phenyl)-3-chloromethyl-[1,2,4]oxadiazole was added to thereaction mixture. The reaction mixture was stirred at room temperatureover night. The reaction mixture was diluted with NH₄Cl(sat) andextracted twice with EtOAc. The combined organic phases were washed withwater, dried and concentrated. Flashchromatography (CH₂Cl₂/MeOH 20:1)afforded 111 mg (32%) of a white solid. 1H NMR (CDCl₃), d (ppm): 2.24(m, 2H) 3.57 (m, 2H) 4.15 (m, 2H) 5.01 (s, 2H) 7.46 (t, 1H) 7.56 (d, 1H)7.62 (d, 2H) 7.99 (d, 1H) 8.10 (s, 1H) 8.70 (d, 2H).

The following compounds were prepared analogously to Example 815:Example No. Name 1H NMR MS 816 8-[5-(5-Chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethyl]-3- pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine 817 8-[5-(3-Chloro-phenyl)-[1,3,4]oxadiazol-2-ylmethyl]-3- pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine 818 8-{1-[5-(3-Chloro-phenyl)- 1.81 (d,3H) 2.19 (m, 2H) [1,3,4]oxadiazol-2-yl]-ethyl}-3- 3.47 (m, 2H)pyridin-4-yl-5,6,7,8-tetrahydro- 4.12 (m, 2H) 6.07 (q, 1H)[1,2,4]triazolo[4,3-a]pyrimidine 7.42 (m, 1H) 7.49 (m, 1H) 7.61 (m, 2H)7.91 (m, 1H) 8.00 (m, 1H) 8.70 (m, 2H) 8198-[5-(5-Chloro-2-fluoro-phenyl)- 2.23 (m, 2H) 3.50 (m, 2H)[1,2,4]oxadiazol-3-ylmethyl]-3-furan- 4.20 (m, 2H) 4.97 (s,2-yl-5,6,7,8-tetrahydro- 2H) 6.49 (m, 1H)[1,2,4]triazolo[4,3-a]pyrimidine 6.89 (d, 1H) 7.19 (t, 1H) 7.48 (m, 1H)7.51/m, 1H) 8.06 (m, 1H) 820 8-{1-[5-(3-Chloro-phenyl)- 1.74 (d, 3H)2.17 (m, 2H) [1,2,4]oxadiazol-3-yl]-ethyl}-3- 3.45 (m, 2H)pyridin-4-yl-5,6,7,8-tetrahydro- 4.10 (m, 2H) 5.96 (m, 1H)[1,2,4]triazolo[4,3-a]pyrimidine 7.44 (t, 1H) 7.53 (m, 1H) 7.59 (m, 2H)7.97 (m, 1H) 8.08 (m, 1H) 8.67 (d, 2H)

Example 8213-(4-Ethyl-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-5-(1H-pyrrol-3-yl)-[1,2,4]oxadiazole

3-Chloromethyl-5-[1-(toluene-4-sulfonyl)-1H-pyrrol-3-yl]-[1,2,4]oxadiazole(50 mg) and potassium hydroxide (50 mg) was heated for two h in methanol(5 ml). The mixture was diluted with ethyl acetate (10 ml), washed withwater and brine, dried over MgSO₄, filtered and concentrated. The titlecompound was isolated in 57% yield by flash chromatography on silica gelusing 40% ethyl acetate in heptane. 1H NMR (CDCl₃) d (ppm): 9.8 (s, 1H),7.5 (m, 2H), 7.4 (d, 1H), 7.2 (dd, 1H), 6.8 (m, 1H), 6.7 (d, 1H), 4.5(s, 2H), 4.1 (q, 2H), 1.4 (t, 3H).

Example 8224-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridine1-oxide

4-{5-[5-(3-Chloro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-4-methyl-4H-[1,2,4]triazol-3-yl}-pyridineand wet 57%-86% MCPBA (52.4 mg, 0.20-0.30 mmol) were dissolved indichloromethane (4 ml) and stirred for 16 h. The reaction mixture waspurified via reversed phase preparative LC to give the title compound(7.5 mg, 8%). 1H NMR (CDCl₃), δ (ppm): 8.33 (d, 2H), 8.06 (m, 1H), 7.96(m, 1H), 7.67 (d, 2H), 7.57 (m, 1H), 7.46 (apparent t, 1H), 4.60 (s,2H), 3.71 (s, 3H).

Example 8235-(3-Chloro-phenyl)-3-(2-furan-2-yl-3-methyl-3H-imidazol-4-ylsulfanylmethyl)-[1,2,4]oxadiazole

2-Furan-2-yl-3-methyl-3,5-dihydro-imidazol-4-one (described in Takeuchi,H., Hagiwara, S., Eguchi, S., Tetrahedron (1989) 6375-6386) (50 mg, 0.30mmol) was dissolved in dioxane (3 ml) and Lawesson reagent (136 mg, 0.34mmol) was added. The reaction mixture was heated to reflux over nightand then allowed to room temperature at which time DIPEA (212 ml, 1.22mmol) and 3-chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (140 mg,0.61 mmol) was added. The resulting mixture was heated to reflux for 5 hand then kept at room temperature over night. Ethyl acetate was addedand the reaction mixture was washed with water followed by brine. Theorganic phase was dried over MgSO₄ and evaporated. The title compound(13 mg, 11%) was obtained by flash chromatography using 1% methanol inchloroform. 1H NMR (CD₃OD) d (ppm): 7.96 (m, 1H), 7.90 (m, 1H), 7.60(dd, 1H), 7.57 (ddd, 1H), 7.46 (t, 1H), 7.09 (s, 1H), 6.86 (dd, 1H),6.52 (dd, 1H), 3.95 (s, 2H), 3.74 (s, 3H).

Example 8245-(5-Chloro-2-fluoro-phenyl)-3-[4-(2-fluoro-ethyl)-5-thiophen-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl]-[1,2,4]oxadiazole

To a cooled (−15° C.) solution of2-{3-[5-(5-chloro-2-fluoro-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-5-thiophen-2-yl-[1,2,4]triazol-4-yl}-ethanol(46 mg, 0.11 mmol) in anhydrous THF (15 ml) was dropwise added DAST (32ml, 0.24 mmol). The mixture was stirred at room temperature for 1.5 hand was then quenched with MeOH (1 ml). The solvent was removed underreduced pressure and the residue was partitioned between brine andEtOAc. The aqueous layer was extracted with EtOAc (2×20 ml). Thecombined organic layers were washed with brine (10 ml), dried (MgSO₄)and concentrated under reduced pressure. Purification by flashchromatography (EtOAc:heptane 2:1) and preparative HPLC afforded thetitle compound as a white solid (11 mg, 22%). 1H NMR (CDCl₃) d (ppm):8.05 (dd, 1H), 7.52 (m, 3H), 7.20 (m, 1H), 7.16 (m, 1H), 4.75 (t, 1H),4.63 (m, 3H), 4.45 (m, 2H).

Example 8255-(5-Chloro-thiophen-3-yl)-3-(4-ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazole

The title compound was prepared according to method for2-[5-(3-Methoxy-phenyl)-[1,2,4]oxadiazol-3-ylmethylsulfanyl]-1H-benzoimidazole,with the exception of using molar equivalent cesium carbonate instead ofpotassium carbonate as the base, from1-[5-(5-chloro-thiophen-3-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-1H-benzotriazole(32.3 mg, 0.097 mmol) and4-ethyl-5-furan-2-yl-2,4-dihydro-[1,2,4]triazole-3-thione (23 mg) byusing 50% EtOAc in n-heptane as chromatography eluent to yield 21 mg. 1HNMR (CDCl₃) d (ppm): 7.95 (d, 1H), 7.57 (dd, 1H), 7.44 (d, 1H), 7.07(dd, 1H), 6.56 (dd, 1H), 4.56 (s, 2H), 4.22 (q, 2H), 1.35 (t, 3H).

Example 8263-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-hydroxy-benzonitrile

The title compound was prepared using the general procedure of Rogers etal., Tetrahedron Letters (2002) 43: 3585-3587. To a stirring solution of3-[3-(4-Ethyl-5-furan-2-yl-4H-[1,2,4]triazol-3-ylsulfanylmethyl)-[1,2,4]oxadiazol-5-yl]-4-fluoro-benzonitrile(20 mg, 0.050 mmol), 2-(methylsulfonyl-ethanol) (9.38 mg, 0.075 mmol),and DMF (0.05 M) at 0° C. was added NaH (5.8 mg, 0.150 mmol). Stirredfor 20 min and removed the ice bath. Stirred an additional 20 min whilewarming to room temperature. The reaction mixture was quenched with 1 NHCl solution and partitioned between ethyl acetate and brine. Theorganic layer was dried (Na₂SO₄), filtered and concentrated to dryness.The crude organics were purified by flash column chromatography usingethyl acetate followed by 5% methanol in ethyl acetate to give the titlecompound (8.1 mg, 41%, white solid). 1H NMR (CDCl₃), δ (ppm): 8.25 (m,1H), 7.75 (m, 1H), 7.60 (s, 1H), 7.18 (m, 2H), 6.60 (m, 1H), 4.64 (s,2H), 4.25 (q, 2H), 1.38 (t, 3H).

Example 8273-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine

KMnO₄ (5 g, 32 mmol) was added to a solution of3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine (6.0 g, 29mmol) in H₂O (40 mL) and acetic acid (100 mL). After 1 h stirring at rtthe reaction was basified with aq. NaOH (4M). CHCl₃ was added and themixture was filtrated through celite. The layers were separated and thewater phase was washed with CHCl₃. The combined organic phase was driedand concentrated to give 3.67 g (53%) of the title compound. ¹H NMR:3.59 (s, 3H) 3.99 (s, 3H) 7.52 (m, 1H) 8.02 (dt, 1H) 8.83 (dd, 1H) 8.91(m, 1H)

The following examples were synthesized in a manner analogous to thatfor 3-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine.Structure Name ¹H-NMR Example No.

3-[4-cyclopropyl-5- (methylsulfonyl)-4H- 1,2,4-triazol-3- yl]pyridine0.98 (m, 2 H) 1.26 (m, 2 H) 3.61 (s, 3 H) 3.68 (m, 1 H) 828

4-[4-methyl-5- (methylsulfonyl)-4H- 1,2,4-triazol-3- yl]pyridine(DMSO-D6): 3.6 (s, 3 H) 3.9 (s, 3 H) 7.8 (s, 2 H) 8.8 (s, 2 H) 829

4-(4-Cyclopropyl-5- methanesulfonyl-4H- 1,2,4-triazol-3-yl)- pyridine8.86 (d, 2 H), 7.77 (d, 2 H), 3.64 (m, 1 H), 3.63 (s, 3 H), 1.25 (m, 2H), 1.01 (m, 2 H). 830

Example 8314-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)-4H-1,2,4-triazole

To 4-methyl-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole (4.15g, 21.0 mmol) in DCM (150 ml) at 0° C. was added mCPBA (57-86%, 15.1 g,52.6 mmol) in portions. After stirring at r.t. o.n. DCM (150 ml) wasadded. The resulting mixture was washed with sat. aq. NaHCO₃, sat. aq.Na₂S₂O₃ and brine, dried and evaporated to afford 4.4 g (91%) of thetitle compound. MS (M⁺−1)=228.

The following examples were synthesized in a manner analogous to thatfor 4-methyl-3-(methylsulfonyl)-5-(trifluoromethyl)-4H-1,2,4-triazole.Structure Name Analytical data Example No.

3-(3,5- difluorophenyl)-4- methyl-5- (methylsulfonyl)-4H- 1,2,4-triazole¹H-NMR (DMSO-D6): 3.60 (s, 3 H) 3.89 (s, 3 H) 7.56 (s, 3 H) MS (M + 1)242 832

3-(4-fluorophenyl)-4- methyl-5- (methylsulfonyl)-4H- 1,2,4-triazole MS(M⁺ + 1) 256 833

Preparation of Intermediate Compounds

Example 834 3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine

MeI (2 mL, 32 mmol) in EtOH (10 mL) was added to a mixture of4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione in 1 MNaOH (70 mL, 70 mmol). After 1 h stirring at rt, DCM was added and thelayers were separated. The water phase was washed with DCM and thecombined organic phases were dried and concentrated to give 6.5 g (98%)of the title compound. ¹H NMR: 2.76 (s, 3H) 3.59 (s, 3H) 7.43 (m, 1H)7.99 (m, 1H) 8.71 (m, 1H) 8.86 (m, 1H)

The following examples were synthesized in a manner analogous to thatfor 3-[4-methyl-5-(methylthio)-4H-1,2,4-triazol-3-yl]pyridine StructureName Analytical data Example No.

3-[4-cyclopropyl-5- (methylthio)-4H- 1,2,4-triazol-3- yl]pyridine LC-MS(M⁺ + 1): 233 835

4-(4-Cyclopropyl-5- methylsulfanyl-4H- 1,2,4-triazol-3-yl)- pyridine ¹HNMR: 8.77 (d, 2 H), 7.75 (m, 2 H), 3.23 (m, 1 H), 2.82 (s, 3 H), 1.17(m, 2 H), 0.80 (m, 2 H). 836

4-[4-methyl-5- (methylthio)-4H- 1,2,4-triazol-3- yl]-pyridine ¹H NMR:(DMSO-D6): 2.7 (s, 3 H) 3.6 (s, 3 H) 7.7 (m, 2 H) 8.8 (d, 2 H) 837

3-(4-fluorophenyl)-4- methyl-5- (methylthio)-4H- 1,2,4-triazole Useddirectly in the next step towards 3-(4- fluorophenyl)-4-methyl-5-(methylsulfonyl)-4H-1,2,4- triazole. 838

Example 8394-methyl-3-(methylthio)-5-(trifluoromethyl)-4H-1,2,4-triazole

4-Methylthiosemicarbazid (10.0 g, 95.09 mmol) in TFA (46.7 ml) washeated to reflux o.n. Excess TFA was removed via evaporation. Theresidue was dissolved in aq. 1M NaOH (100 ml), followed by dropwiseaddition of CH₃I (4.47 ml, 71.17 mmol) in EtOH (22 ml). The resultingmixture was stirred o.n. Partial evaporation of the solvent inducedcrystallization. After dilution with H₂O the solid was collected viafiltration and gave after drying the title compound (5.2 g, 28%). MS(M⁺+1) 198

Example 8403-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole

The title compound was obtained as a byproduct in the synthesis of5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine. ¹H NMR(DMSO-D6): 2.66 (s, 3H) 3.60 (s, 3H) 7.43-7.52 (m, 3H). MS (M⁺+1) 242.

Example 8414-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione

Nicotinohydrazide (10 g, 73 mmol) and methyl isothiocyanate (5.6 g, 76mmol) were mixed in 2-propanol (150 ml) and heated to 70° C. o.n. Thereaction was cooled to r.t. and evaporated to dryness. H₂O (180 mL) andNaHCO₃ (12.8 g, 152 mmol) were added to the residue and the mixture wasrefluxed o.n. The reaction mixture was cooled to rt, acidified withconcentrated hydrochloric acid and the title compound, 13.1 g (93%), wascollected by filtration. LC-MS (M⁺+1): 193

The following examples were synthesized in a manner analogous to thatfor 4-methyl-5-pyridin-3-yl-2,4-dihydro-3H-1,2,4-triazole-3-thioneStructure Name Analytical data Example No.

4-cyclopropyl-5- pyridin-4-yl-2,4- dihydro-3H-1,2,4- triazole-3-thione¹H-NMR: 0.63 (m, 2 H) 1.00 (m, 2 H) 3.25 (m, 1 H) 7.75 (d, 2 H) 8.74 (m,2 H) 842

4-cyclopropyl-5- pyridin-3-yl-2,4- dihydro-3H-1,2,4- triazole-3-thioneLC-MS (M⁺ + 1): 219 843

Example 8445-(4-fluorophenyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione

To 4-methylthiosemicarbazid (4.24 g, 40.30 mmol) in pyridine (50 ml) wasadded dropwise 4-fluorobenzoyl chloride (4.9 ml, 40.00 mmol) and theresulting mixture was stirred at r.t. o.n. The pyridine was removed byevaporation and the residue was heated in aq. sat. NaHCO₃ at reflux o.n.After cooling to r.t., the product was collected by filtration, washedwith water and dried under vacuum to give 3.22 g (38%) which was used inthe next step without further purification. ¹H NMR: 3.9 (m, 3H) 6.98 (t,2H) 7.92 (m, 2H).

Example 845 N′-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide

6.45 g crude N′,2-dihydroxypropanimidamide was cooled on an ice-bathwith 23.5 mL DEA in THF (200 mL). To this slurry 21.94 g 3-chlorobenzoylchloride was added. The mixture was warmed to r.t. and stirred for 2 h.Addition of Et₂O (200 mL), washing with sat. aq. NH₄Cl and re-extractionof the aq. layer gave after combining and concentration of the org.layers followed by drying in vacuo 27.24 g of crude title compound,which was used directly in the next step for1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. LC-MS (M⁺+1): 243

Example 8463-chloro-N′-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamide

3.82 g (22.4 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide and 2.00g (22.2 mmol) of (R)-lactic acid were dissolved under Ar at 0° C. in DCM(50 mL) and DMF (15 mL). After 5 min 3.4 mL (33.2 mmol) DIC and 3.50 g(25.9 mmol) HOBt were added. After 15 min the mixture was warmed to r.t.and stirred for additional 3 h, followed by filtration and washing withDCM. The filtrate was evaporated in vacuo to near dryness, taken up inEA and washed with aq. NaHCO₃, followed by water and finally 2 M aq.citric acid. The EA layer was filtered over a mixture of Na₂SO₄ andsilica. Flash chromatography (Hep/EA=4/1 to 2/1 to 1/2) gave an oilwhich was triturated with Et₂O to yield after drying 4 g (75%) of thetitle compound. ¹H NMR: 7.69 (t, 1H), 7.55-7.59 (m, 1H), 7.44-7.49 (m,1H), 7.36 (t, 1H), 5.10 (s, 2H), 4.50 (q, 1H), 1.54 (d, 3H)

Example 847 N′,2-dihydroxypropanimidamide

44.2 g (0.64 mol) of hydroxylamine hydrochloride and 25.5 g (0.64 mol)sodium hydroxide were dissolved in ethanol (500 mL) at r.t. and stirredfor 3 h. After filtration, 8.11 g (0.11 mol) 2-hydroxypropanenitrilewere added to the filtrate, followed by stirring for 4 h. Afterconcentration to dryness the title compound was obtained which wasdirectly used in the next step. ¹H NMR (DMSO-D6): 8.88 (s, 1H), 5.15 (s,1H), 5.02 (s, 1H), 4.00 (q, 1H), 1.19 (d, 3H).

Example 8481-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine

MeNH₂ in EtOH (6 mL, 8 M, 48 mmol) was added to3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.5 g, 6.5 mmol)in EtOH (20 mL). After 20 h the solvent was evaporated and the residuewas dried in vacuum to give 1.47 g (100%) of the title compound. LC-MS(M⁺+1): 224

The following examples were synthesized in a manner analogous to thatfor 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine.Example Structure Name ¹H-NMR No.

[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]- cyclopropyl-amine8.05 (s, 1 H), 7.95 (d, 1 H), 7.42 (d, 1 H), 7.39 (t, 1 H), 4.08 (s, 2H), 2.89 (m, 1 H), 1.75 (brs, 1 H), 1.09 (d, 6 H). 849

{1-[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-yl]-ethyl}-cyclopropyl-amine 8.12 (s, 1 H), 8 (d, 1 H), 7.45 (d, 1 H), 7.4 (t, 1H), 4.2 (q, 1 H), 2.14 (brs, 1 H), 2.04 (m, 1 H), 1.54 (d, 3 H), 0.43(brm, 4 H). 850

[5-(3-Chloro-phenyl)- isoxazol-3-ylmethyl]-methyl- amine 7.78 (m, 1 H),7.67 (m, 1 H), 7.42 (m, 2 H), 6.58 (s, 2 H), 3.90 (s, 2 H), 2.53 (s, 3H). 851

{1-[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-yl]-ethyl}- methyl-amine8.03 (s, 1 H), 7.9 (d, 1 H), 7.41 (d, 1 H), 7.37 (t, 1 H), 1.04 (q, 1H), 2.4 (s, 3 H), 1.6 (br, 1 H), 1.51 (d, 3 H). 852

[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]- ethyl-amine 8.02 (s,1 H), 7.9 (d, 1 H), 7.42 (d, 1 H), 7.35 (t, 1 H), 4.06 (s, 2 H), 2.72(q, 2 H), 1.73 (br. m, 1 H), 1.11 (t, 3 H). 853

[3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]- isopropyl-amine 7.98(s, 1 H), 7.87 (d, 1 H), 7.35 (d, 1 H), 7.31 (t, 1 H), 4.04 (s, 2 H),2.23 (brs, 1 H), 2.2 (m, 1 H), 0.37 (m, 4 H). 854

3-(3-Chloro-phenyl)- [1,2,4]oxadiazol-5-ylmethyl]- methyl-amine 8.13 (S,1 H), 8.00 (d, 1 H), 7.52 (dm, 1 H), 7.47 (t, 1 H), 4.11 (s, 2 H), 2.58(s, 3 H). 855

Example 856N-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N′-cyclopropyl-N-methylthiourea

Cyclopropyl isothiocyanate (650 mg, 6.6 mmol) was added to1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]-N-methylmethanamine (1.47g, 6.5 mmol) in EtOH (20 mL). After 3 h the formed precipitate wasfiltrated off and washed with cold EtOH to give 1.63 g (78%) of thetitle compound. LC-MS (M⁺+1): 323.

The following examples were synthesized in a manner analogous to thatforN-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N′-cyclopropyl-N-methylthiourea.Structure Name ¹H-NMR Example No.

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-cyclopropyl-3-methyl- thiourea 8.07 (s, 1 H), 7.96 (d, 1 H),7.48 (d, 1 H), 7.41 (t,1 H), 6.82 (br, 1 H), 5.48 (s, 2 H), 3.25 (d, 3 H), 2.91 (br, 1 H), 1.05(br, 4 H). 857

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-ethyl-3-methyl-thiourea 8.08 (s, 1 H), 7.96 (d, 1 H), 7.48 (d, 1 H), 7.45 (t, 1H), 6.1 (br, 1 H), 5.38 (s, 2 H), 3.73 (q, 2 H), 3.21 (d, 3 H), 1.33 (t,3 H). 858

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-isopropyl-3-methyl-thiourea 8.05 (s, 1 H), 7.93 (d, 1 H), 7.48 (d, 1 H), 7.42 (t, 1H), 6.45 (br, 1 H), 5.04 (s, 2 H), 4.96 (m, 1 H), 3.21 (d, 3 H), 1.26(m, 4 H). 859

1-[5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]-1,3- dimethyl- thiourea¹H NMR (DMSO-d6): 7.98 (m, 1 H), 7.84 (m, 1 H), 7.72 (m, 1 H), 7.56 (m,2 H), 7.06 (s, 1 H), 5.19 (s, 2 H), 3.08 (s, 3 H), 2.94 (s, 3 H). 860

1-{1-[3-(3- Chloro- phenyl)- [1,2,4]oxadiazol- 5-yl]-ethyl}-1-cyclopropyl- 3-methyl- thiourea 8.00 (s, 1 H), 7.98 (d, 1 H), 7.47 (d,1 H), 7.44 (t, 1 H), 7.25 (m, 1 H), 6.84 (br, 1 H), 3.26 (d, 3 H), 2.55(br, 1 H), 1.9 (d, 3 H), 0.91 (br, 2 H), 0.76 (br, 2 H). 861

1-{1-[3-(3- Chloro- phenyl)- [1,2,4]oxadiazol- 5-yl]-ethyl}-1,3-dimethyl- thiourea 8.05 (s, 1 H), 7.95 (d, 1 H), 7.46 (d, 1 H), 7.4(t, 1 H), 5.99 (br, 1 H), 3.21 (d, 3 H), 3.15 (s, 3 H), 1.72 (d, 3 H),1.4 (q, 1 H). 862

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1,3-dimethyl-thiourea 8.09 (s, 1 H), 7.98 (d, 1 H), 7.51 (d, 1 H), 7.46 (t, 1 H),5.91 (w, 1 H), 5.55 (s, 2 H), 3.32 (s, 3 H) and 3.23 (d, 3 H). 863

Example 8641-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-3-cyclopropyl-1-methyl-thiourea

3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-methyl-amine (415 mg,1.85 mmol) was mixed with cyclopropylisothiocyanate (220 mg, 2.22 mmol)in chloroform (5 mL) at r.t. for 2 hours. The reaction mixture wasconcentrated and the residue was triturated with Et₂O to yield the titlecompound (406 mg, 67.9%). ¹H-NMR: 8.09 (s, 1H), 7.98 (d, 1H), 7.51 (d,1H), 7.46 (t, 1H), 6.00 (w, 1H), 5.53 (s, 2H), 3.28 (s, 3H), 3.11 (m,1H), 2.45 (s, 3H), 0.94 (m, 2H) and 0.69 (m, 2H).

Example 865 MethylN-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N′-cyclopropyl-N-methylimidothiocarbamate

MeI (320 μL, 5.1 mmol) andN-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N′-cyclopropyl-N-methylthiourea(1.59 g, 4.9 mmol) were mixed in EtOH (20 mL) and heated to 70° C. for 2h. The reaction was cooled to r.t. and NaOH (1M) was added until pH=10.EA was added and the mixture was stirred for 5 min. The layers wereseparated and the water phase was extracted with EA. The organic phasewas dried and concentrated. The product was purified by columnchromatography (Hep-EA 1:1) to afford 960 mg (59%) of the titlecompound. LC-MS (M⁺+1): 337

The following examples were synthesized in a manner analogous to thatfor methylN-{[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]methyl}-N′-cyclopropyl-N-methylimidothiocarbamate.Structure Name ¹H-NMR Example No.

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1,2,3-trimethyl-isothiourea 8.09 (s, 1 H), 7.98 (d, 1 H), 7.50 (d, 1 H), 7.45 (t, 1 H),4.85 (s, 2 H), 3.23 (s, 3 H), 3.11 (d, 3 H) and 2.37 (s, 3 H). 866

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-cyclopropyl-2,3-dimethyl- isothiourea 8.07 (s, 1 H), 7.96 (d, 1 H), 7.47 (d, 1 H),7.44 (t, 1 H), 4.84 (s, 2 H), 3.23 (s, 3 H), 2.85 (m, 1 H), 2.37 (s, 3H), 0.83 (m, 2 H), 0.68 (m, 2 H). 867

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 1-ethyl-2,3-dimethyl- isothiourea 8.08 (s, 1 H), 7.96 (d, 1 H), 7.46 (d, 1 H), 7.44(t, 1 H), 4.79 (s, 2 H), 3.58 (q, 2 H), 3.2 (s, 3 H), 2.38 (s, 3 H), 1.2(t, 3 H). 868

1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]- 3-cyclopropyl-1,2-dimethyl- isothiourea 8.09 (s, 1 H), 7.98 (d, 1 H), 7.51 (d, 1 H),7.44 (t, 1 H), 4.78 (s, 2 H), 3.17 (m, 1 H), 3.13 (s, 3 H), 2.43 (s, 3H), 0.72 (m, 2 H) and 0.56 (m, 2 H). 869

1-[5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]- 1,2,3-trimethyl-isothiourea 7.70 (m, 1 H), 7.67 (m, 1 H), 7.42 (m, 2 H), 6.51 (s, 1 H),4.67 (s, 2 H), 3.31 (s, 3 H), 2.94 (s, 3 H), 2.37 (s, 3 H). 870

1-{1-[3-(3- Chloro- phenyl)- [1,2,4]oxadiazol- 5-yl]-ethyl}-1,2,3-trimethyl- isothiourea 8.09 (s, 1 H), 7.98 (d, 1 H), 7.47 (d, 1H), 7.45 (t, 1 H), 5.75 (br, 1 H), 3.26 (s, 3 H), 2.91 (s, 3 H), 2.39(s, 3 H), 1.7 (d, 3 H). 871

Example 8721-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-2-ethyl-3-methyl-isothiourea

1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-3-methyl-thiourea(287 mg, 0.85 mmol) was mixed with iodoethane (484 mg, 3.4 mmol) in MeOH(5 mL) at 60° C. overnight. The reaction mixture was concentrated andbasified with saturated sodium carbonate, then extracted with DCM. Theorganic layer was dried, concentrated to give the title compound (298mg, 96%). ¹H-NMR: 8.11 (s, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.46 (t,1H), 5.51 (m, 1H), 3.27 (s, 3H), 2.85-3.00 (m, 2H), 2.60 (m, 1H), 1.79(d, 3H), 1.30 (t, 3H), 0.83 (m)

Example 8731-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-2-ethyl-1-isopropyl-3-methyl-isothiourea

The title compound was synthesized analogous to1-{1-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-ethyl}-1-cyclopropyl-2-ethyl-3-methyl-isothiourea.¹H-NMR: 8.09 (s, 1H), 7.97 (d, 1H), 7.50 (d, 1H), 7.44 (t, 1H), 4.87 (m,1H), 4.66 (s, 2H), 3.15 (s, 3H), 2.88 (q, 2H), 1.35 (t, 3H) and 1.23 (s,6H)

Example 874 methyl N-cyclopropyl-N′-methylimidothiocarbamate hydroiodide

MeI (265 ml, 4.2 mmol) was added to N-cyclopropyl-N′-methylthiourea (500mg 3.8 mmol) in acetone (10 ml) and the mixture was heated to reflux.After stirring for 20 min heating was stopped and the solvent wasremoved under reduced pressure giving the crude title compound in 960 mgyield that was used directly in the next step.

Example 875 N-cyclopropyl-N′-methylcarbonohydrazonic diamide hydroiodide

Crude methyl N-cyclopropyl-N′-methylimidothiocarbamate hydroiodide (960mg, 3.5 mmol) was mixed with hydrazine hydrate (240 ml, 3.9 mmol) inethanol and heated to reflux for 3 h. The mixture was kept at 7° C. for12 h, yielding crude title compound (0.9 g) which was used directly inthe next step.

Example 876 5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine

To a solution of methyl N,N′-dimethylimidothiocarbamate hydroiodide (5.0g, 20.3 mmol) in pyridine (30 ml) was added 3,5-difluorobenzohydrazide(3.5 g, 20.3 mmol) and the mixture was heated to reflux for 24 h. Aftercooling to r.t. the reaction mixture was poured into ice/H₂O, the formedprecipitate was removed via filtration. The filtrate was extracted withCHCl₃, the organic phase was dried and concentrated. The residue waswashed with Et₂O and then purified by column chromatography usingCHCl₃:MeOH=99:1 to 10:1. The title compound was obtained (0.83 g, 18%)together with3-(3,5-difluorophenyl)-4-methyl-5-(methylthio)-4H-1,2,4-triazole (0.44g, 9%) as a byproduct. ¹H NMR (DMSO-D6): 2.83 (d, 3H) 3.41 (s, 3H) 6.20(d, 1H) 7.35 (m, 3H), MS (M⁺+1) 225.

Example 877Methyl-(4-methyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-amine

A mixture of 1000 mg (4.35 mmol) N-amino-N′,N″-dimethyl-guanidinehydriodide (Henry; Smith; J. Amer. Chem. Soc.; 73; 1951; 1858) and 774mg (4.35 mmol) isonicotinoyl chloride hydrochloride in pyridine (3 mL)was heated under microwave irradiation for 5 min at 160° C. Aq. sat.K₂CO₃ was added and the mixture was extracted with CHCl₃. The organicphase was dried and concentrated. Recrystallization from EtOH, water andEA gave 216 mg (26%) of the title compound. ¹H NMR (DMSO-d6): 2.85 (d,3H) 3.45 (s, 3H) 6.25 (d, 1H) 7.65 (m, 2H) 8.67 (m, 2H).

Example 8783-pyridin-4-yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine

A solution of 750 mg (3.1 mmol)(1,4,5,6-tetrahydro-pyrimidin-2-yl)-hydrazine hydroiodide (Krezel,Izabella; Pharmazie; 1994; p. 27-31) and 552 mg (3.1 mmol) isonicotinoylchloride hydrochloride in 3 ml pyridine was heated at 120° C. o.n. Thereaction mixture was cooled and diluted with aq. sat. K₂CO₃ andextracted with chloroform. The combined organic extracts were dried andconcentrated. Flash chromatography (DCM/MeOH 10:1) afforded 83 mg (18%)of the title compound. ¹H NMR: 1.91 (m, 2H) 3.24 (m, 2H) 4.13 (m, 2H)7.67 (m, 2H) 8.65 (m, 2H)

Example 879 N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine

A mixture of N-amino-N′,N″-dimethyl-guanidine (500 mg, 2.17 mmol) [J.Amer. Chem. Soc.; 1951; p. 1858] and nicotinoyl chloride hydrochloride(385 mg, 2.17 mmol) in pyridine (10 mL) was refluxed o.n. Aq. sat. K₂CO₃was added and the mixture extracted with CHCl₃. The organic phase wasdried and concentrated. The crude product 240 mg (61%) was used in thenext step without further purifications. LC-MS (M⁺+1): 190

Example 880N-cyclopropyl-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

Isonicotinoyl chloride hydrochloride (630 mg, 3.5 mmol) was added toN-cyclopropyl-N′-methylcarbonohydrazonic diamide hydroiodide (900 mg 3.5mmol) in pyridine (10 ml) and the mixture was stirred at r.t. for 2 h.The mixture was the heated to 160° C. under microwave irradiation for 10min. Water (50 ml) was added and the mixture was extracted with DCM. Thepooled organic phases were dried and concentrated and the desiredproduct was obtained by prep. HPLC. LCMS (M⁺+1) 216

Example 8815-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine

2-Chloroisonicotinic acid (2.2 g, 13.8 mmol) was refluxed in thionylchloride (50 ml) for 5 h. The solvent was evaporated (coevaporation withtoluene) and the residue was dissolved in pyridine (25 ml) and added inportions to N,N′-dimethylcarbonohydrazonic diamide hydroiodide (3.0 g,13.0 mmol) dissolved in pyridine (25 ml). The reaction mixture washeated at 120° C. overnight and the solvent was evaporated, followed byaddition of water (10 ml) and filtration. The remaining aq. solution waspurified by prep HPLC to give 0.54 g (19%) of the intermediate5-(2-chloropyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine. ¹H-NMR(DMSO-d6): 8.51 (dd, 1H), 7.76 (m, 1H), 7.71 (dd, 1H), 6.37 (m, 1H),3.49 (s, 3H), 2.86 (d, 3H). This intermediate (0.52 g, 2.3 mmol) wasdissolved in MeOH (35 ml) and sodium methoxide (4.4 ml of a 30% solutionin MeOH, 23.3 mmol) was added. The mixture was refluxed o.n., added tobrine and extracted with CHCl₃. The combined organic layers were dried(MgSO₄) and concentrated to give the title compound (0.28 g, 55%). ¹HNMR (DMSO-d6): 8.26 (d, 1H), 7.27 (dd, 1H), 7.05 (m, 1H), 6.26 (q, 1H),3.90 (s, 3H), 3.44 (s, 3H), 2.85 (d, 3H).

Example 882 4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine

Oxalyl chloride (860 ml, 10 mmol) was slowly added to a solution ofN-cyclopropylacetamide (1 g, 10 mmol) [Bouzoubaa, Mohamed, J. Med.Chem.; 28; 7; 1985; 896-900]. and 2,6-lutidine (2.33 ml, 20 mmol) in DCM(30 ml) at r.t. After stirring for 30 min isonicotinic acid hydrazide(1.37 g, 10 mmol) was added. The mixture was stirred at r.t. for 3hours. The solvent was then removed under reduced pressure. Aq. sat.sodium carbonate (15 ml) was added and the mixture was heated to refluxfor 2 h, then extracted with EA. The combined organic phases were driedand concentrated. The resulting solid was recrystallized from EA givingthe title compound in 1.1 g yield. ¹H NMR: 0.7 (m, 2H) 1.2 (m, 2H) 2.6(s, 3H) 3.3 (ddd, 1H) 7.7 (m, 2H) 8.7 (d, 2H)

The following examples were synthesized in a manner analogous to thatfor 4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine. StructureName ¹H-NMR Example No.

4-(4- cyclopropyl-5- ethyl-4H-1,2,4- triazol-3- yl)pyridine 0.69 (m, 2H) 1.15 (d, 2 H) 1.48 (t, 3 H) 1.66 (s, 2 H) 2.95 (q, 2 H) 3.28 (s, 1 H)7.71 (d, 2 H) 8.75 (d, 2 H) 883

4-(4,5- dimethyl-4H- 1,2,4-triazol-3- yl)pyridine 8.76 (dd, 2 H),7.52-7.63 (m, 2 H), 3.66 (s, 3 H), 2.52 (s, 3 H) 884

Example 8853-[3-Cyclopropyl-2-(2,6-dichloro-pyridin-4-yl)-3H-imidazol-4-yl]-2-methyl-acrylicacid ethyl ester

3-cyclopropyl-2-(2,6-dichloro-pyridin-4-yl)-3H-imidazole-4-carbaldehyde(1.48 g, 5.25 mmol), triethyl-2-phosphonopropionate (1.46 ml, 6.83 mmol)and DBU (1.02 ml, 6.83 mmol) were dissolved in acetonitrile (20 ml).After stirring at 78° C. o.n. the reaction mixture was cooled to r.t,diluted with water and extracted with DCM. The combined organic phasewas dried (Na₂SO₄), filtered and concentrated in-vacuo. The crude waspurified on silica gel using 6% EA in DCM, and the isolated residue wastriturated with hex. to isolate the title compound (1.66 g, 86%).¹H-NMR: 7.86 (m, 1H), 7.75 (d, 2H), 7.43 (s, 1H), 4.34 (q, 2H), 3.45 (m,1H), 2.19 (s, 3H), 1.39 (t, 3H), 1.29 (m, 2H), 0.78 (m, 2H).

Example 8863-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-acrylic acidethyl ester

3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde (500 mg,2.06 mmol), triethyl phosphonoacetate (0.53 ml, 2.68 mmol) and DBU (0.40ml, 2.68 mmol) were dissolved in acetonitrile (5 ml). After stirring at78° C. o.n. the reaction mixture was cooled to r.t., diluted with water(50 ml), extracted with DCM. The combined organic phase was dried(Na₂SO₄), filtered and concentrated in-vacuo. Purification of the crudeon silica gel using 50% EA in hex. gave the title compound (471 mg,73%). ¹H-NMR: 7.85 (d, 1H), 7.79 (d, 2H), 7.49 (s, 1H), 7.00 (d, 2H),6.36 (d, 1H), 4.31 (q, 2H), 3.89 (s, 3H), 3.39 (m, 1H), 1.36 (t, 3H),1.14 (m, 2H), 0.69 (m, 2H).

Example 8873-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-acrylicacid ethyl ester

(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol (6.8 g,31.4 mmol) was mixed with MnO₂ (40 g, 0.46 mol) in acetonitrile at r.t.for 2 hours and then heated at 80° C. for another 30 min. The reactionmixture was filtered through celite. The filtrate was mixed with2-(diethoxy-phosphoryl)-propionic acid ethyl ester (12.35 g, 51.8 mmol)and DBU (7.17 g, 47 mmol) at 80 to 90° C. for 4 h. The reaction mixturewas concentrated, dissolved in EA and washed with water and brine. Theorganic layer was dried, concentrated and triturated with hex. to givethe title compound in 5.76 g (61%) yield. ¹H-NMR: 8.78 (d, 2H), 7.78 (d,2H), 7.67 (s, 1H), 4.32 (q, 2H), 3.43 (m, 1H), 2.53 (s, 3H), 1.38 (t,3H), 1.24 (m, 2H) and 0.73 (m, 2H).

Example 8883-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-propionicacid ethyl ester

3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde (475 mg,1.96 mmol), triethyl-2-phosphonopropionate (0.63 ml, 2.94 mmol) and DBU(0.44 ml, 2.94 mmol) were dissolved in acetonitrile (5 ml). Afterstirring at 78° C. o.n. the reaction mixture was cooled to r.t., dilutedwith water (50 ml) and extracted with DCM. The combined organic phasewas dried (Na₂SO₄), filtered and concentrated, to yield3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-acrylicacid ethyl ester, which was dissolved in ethanol and hydrogenated atatmospheric pressure over 10% Pd/C (0.5 g) for 24 h. The reactionmixture was filtered through a celite pad and concentrated. Afterpurification on silica gel (EA/DCM=1/1) the isolated product wasdissolved in Et₂O (10 ml) and treated with HCl (1N in Et₂O, 4 ml). Theresulting mixture was concentrated and the isolated residue wastriturated with Et₂O to isolate the title compound solid (466 mg).¹H-NMR: 7.90 (d, 2H), 7.10 (m, 3H), 4.16 (m, 2H), 3.90 (s, 3H), 3.47 (m,1H), 3.24 (m, 1H), 2.85 (m, 2H), 1.37 (d, 3H), 1.27 (m, 5H), 0.75 (m,2H).

Example 8893-[2-(4-Methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]-2-methyl-propionicacid ethyl ester

The title compound was synthesized analogous to3-[3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-2-methyl-propionicacid ethyl ester. ¹H-NMR: 7.52 (dd, 2H), 6.99 (dd, 2H), 6.88 (s, 1H),4.15 (q, 2H), 3.87 (s, 3H), 3.59 (s, 3H) 3.00 (m, 1H), 2.80 (m, 1H),2.67 (m, 1H), 1.27 (m, 6H).

Example 8903-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionicacid ethyl ester

3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-acrylicacid ethyl ester (5.76 g, 19.3 mmol) was hydrogenated with 10% Pd/C (3.0g) in EtOH (100 ml) o.n. The reaction mixture was filtered andconcentrated. The residue was triturated with hex. to give the titlecompound in 3.1 g (53%) yield. ¹H-NMR: 8.76 (d, 2H), 7.73 (d, 2H), 4.14(m, 2H), 3.35 (m, 3H), 2.88 (q, 1H), 1.39 (d, 3H), 1.25 (t, 3H), 1.18(m, 2H) and 0.73 (m, 2H).

The following examples were synthesized analogous to3-(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionicacid ethyl ester Structure Name ¹H-NMR Example No.

3-(3- Cuclopropyl-2- pyridin-4-yl- 3H-imidazol-4- yl)-2-methyl-propionic acid ethyl ester 8.69 (dd, 2 H), 7.68 (dd, 2 H), 6.91 (s, 1H), 4.16 (q, 2 H), 3.33 (m, 1 H), 3.19 (m, 1 H), 2.85 (m, 2 H), 1.33 (d,3 H), 1.25 (t, 3 H), 1.14 (m, 2 H), 0.69 (m, 2 H). 891

3-[3- Cyclopropyl-2- (4-methoxy- phenyl)-3H- imidazol-4-yl]- propionicacidethyl ester 7.66 (d, 2 H), 6.95 (d, 2 H), 6.80 (br. s, 1 H), 4.20(q, 2 H), 3.88 (s, 3 H), 3.23 (m, 1 H), 3.05 (m, 2 H), 2.76 (m, 2 H),1.30 (t, 3 H), 1.03 (m, 2 H), 0.65 (m, 2 H). 892

Example 8933-(3-Cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionicacid

3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionicacid ethyl ester (1.02 g, 3.40 mmol) was mixed with MeOH (8 ml) andsodium hydroxide (1N in water, 5.1 ml, 5.10 mmol). This mixture was leftstirring at r.t. for 5 h, followed by concentration in-vacuo. Theisolated residue was treated with aq. HCl (2N, 6 ml) to isolate thetitle compound (702 mg, 76%). ¹H-NMR (DMSO-d6): 8.63 (dd, 2H), 7.74 (dd,2H), 6.82 (s, 1H), 3.55 (m, 1H), 3.09 (m, 1H), 2.82 (m, 2H), 1.19 (d,3H), 1.08 (m, 2H), 0.56 (m, 2H).

Example 8943-[2-(4-Methoxy-phenyl)-3-methyl-3H-midazol-4-yl]-2-methyl-propionicacid

The title compound was synthesized analogous to3-(3-Cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionicacid. ¹H-NMR (DMSO-d6): 7.52 (d, 2H), 7.02 (d, 2H), 6.71 (s, 1H), 3.80(s, 3H), 3.55 (s, 3H) 2.89 (m, 1H), 2.67 (m, 2H), 1.15 (d, 3H).

Example 8953-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde

N-cyclopropyl-4-methoxy-benzamidine (0.90 g, 4.75 mmol),2-bromo-3-isopropoxy-propenal (1.37 g, 7.12 mmol) and K₂CO₃ (0.98 g,7.12 mmol) were mixed with chloroform (10 ml) and water (1.2 ml),followed by stirring at r.t. for 24 h. After drying of the reactionmixture (Na₂SO₄), filtration and concentration of the filteratein-vacuo, the crude residue was purified via flash chromatography (40%EA in hex.) to isolate the title compound (973 mg, 85%). ¹H-NMR: 9.83(s, 1H), 7.82 (m, 3H), 7.02 (d, 2H), 3.89 (s, 3H), 3.58 (m, 1H), 1.13(m, 2H), 0.64 (m, 2H).

The following examples were synthesized in a manner analogous to thatfor 3-Cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazole-4-carbaldehyde.Structure Name ¹H-NMR Example No.

3-Cyclopropyl- 2-(2,6- dichloro- pyridin-4-yl)- 3H-imidazole-4-carbaldehyde 9.92 (s, 1 H), 7.88 (s, 1 H), 7.79 (s, 2 H), 3.65 (m, 1H), 1.33 (m, 2 H), 0.72 (m, 2 H). 896

2-(4-methoxy- phenyl)-3- methyl-3H- imidazole-4- carbaldehyde 9.77 (s, 1H), 7.87 (s, 1 H), 7.63 (dd, 2 H), 7.04 (dd, 2 H), 4.02 (s, 3 H), 3.89(s, 3 H). 897

Example 898(4-Cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-methanol

4-(4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine (6.85 g, 36.8 mmol)was mixed with 37% formaldehyde (30 mL) in a sealed vial and heated at135° C. o.n. The reaction mixture was concentrated with silica gel andthen mixed with MeOH. The mixture was filtered and washed with MeOH. Thefiltrate was concentrated with silica gel again and loaded on a flashcolumn and eluted with 10% MeOH (2 M NH₃) in DCM to give the titlecompound (6.8 g, 85%). ¹H-NMR (DMSO-d₆): 8.75 (d, 2H), 7.84 (d, 2H),5.63 (t, 1H), 4.72 (d, 2H), 3.66 (m, 1H), 1.04 (m, 2H), 0.73 (m, 2H).

Example 899 3-chloro-N′-hydroxybenzenecarboximidamide

A solution of 3.35 mL (30.0 mmol) 3-chlorobenzonitrile in ethanol (40mL) was added to a solution of 2.47 g (35.5 mmol) hydroxylaminehydrochloride and 1.42 g (35.5 mmol) NaOH in water (20 mL) at r.t. andthen heated at 90° C. for 24 h. After cooling, the reaction mixture wasconcentrated, the residue diluted with water, followed by filtration anddrying to afford 1.13 g (93%) of the title compound. ¹H NMR: 8.11 (s,1H), 7.72 (s, 1H), 7.61 (m, 1H), 7.46 (m, 1H), 7.36 (m, 1H).

Example 900 N-Cyclopropyl-4-methoxy-benzamidine

4-methoxy-benzimidic acid ethyl ester hydrochloride (1.25 g, 5.8 mmol),DCM (5 ml) and cyclopropylamine (0.92 ml, 13.3 mmol) were mixed. Afterstirring at r.t for 3 h, the reaction mixture was concentrated in-vacuo.The residue was treated with cold aq. sodium hydroxide (IM) andextracted with EA. The combined organic phase was washed with water andbrine, dried (Na₂SO₄), filtered and concentrated in-vacuo, to isolatethe title compound (0.90 g, 82%). ¹H-NMR: 7.64 (d, 2H), 6.90 (d, 2H),5.3 (bs, 2H), 3.85 (s, 3H), 2.59 (m, 1H), 0.84 (m, 2H), 0.62 (m, 2H).

Example 901 4-Methoxy-N-methyl-benzamidine

Methylamine hydrochloride (2.28 g, 33.8 mmol) was suspended in toluene(16 ml). After cooling the resulting mixture to 0° C., trimethylaluminum(2M in toluene) was added drop-wise under Ar, followed by warming themixture to r.t and stirring for 2 h. To this mixture was then added asolution of 4-methoxybenzonitrile in toluene (16 ml), followed bystirring at 80° C. for 24 h. The reaction mixture was cooled to r.t. andslowly poured in to a slurry of silica gel (10 g) in CHCl₃ (75 ml). Theslurry was stirred at r.t for 15 minutes and filtered using MeOH. Thefiltrate was concentrated. The isolated residue was dissolved in water(50 ml) and extracted with CHCl₃. The combined organic phase was washedwith brine, dried (Na₂SO₄), filtered and concentrated in-vacuo, toisolate the title compound (1.25 g). ¹H-NMR (DMSO-d6): 7.68 (d, 2H),6.91 (dd, 2H), 6.33 (br. s, 2H), 3.77 (s, 3H), 2.77 (s, 3H)

Example 902 2,6-Dichloro-N-cyclopropyl-isonicotinamidine

2,6-dichloropyridine-4-carbonitrile (5 g, 28.9 mmol), methanol (50 ml)and sodium methoxide (0.66 ml, 2.89 mmol) were mixed and stirred at r.t.for 3 h. HCl in EtOH (24% w/w, 10 ml) and cyclopropylamine (3 mL, 43.4mmol) were added at 0° C., followed by stirring at r.t. o.n. Thereaction mixture was concentrated in-vacuo. The isolated residue wastreated with cold aq. NaOH (1N, 75 ml) and extracted with EA. Thecombined organic phase was washed sequentially with aq. NaOH and brine,dried (Na₂SO₄), filtered and concentrated in-vacuo. The isolated residuewas triturated with Et₂O to isolate the title compound (3.82 g). ¹H-NMR:7.59 (br. s, 2H), 4.96 (br. s, 2H), 2.60 (m, 1H), 0.90 (m, 2H), 0.69 (m,2H).

Example 903 4-Methoxy-benzimidic acid ethyl ester hydrochloride

4-Methoxybenzonitrile and 24% hydrochloric acid in EtOH were mixed at 0°C. This mixture was left stirring at r.t. o.n., followed byconcentration in-vacuo. The isolated residue was triturated with Et₂O toisolate the title compound (1.25 g). ¹H-NMR: 12.3 (br. s, 1H), 11.6 (br.s, 1H), 8.43 (d, 2H), 7.04 (d, 2H), 4.91 (t, 3H), 3.90 (s, 3H), 1.61 (t,3H).

Example 904 2-Bromo-3-isopropoxy-propenal

A mixture of 2-bromomalonaldehyde, para-toluenesulfonic acidmonohydrate, 2-propanol and cyclohexane were stirred at 86° C. in flaskwith a dean-stark trap under azeotropic conditions. Further distillationremoved another 40% of the original solvent volume. The mixture wascooled to 0° C., then concentrated in-vacuo, to isolate the titlecompound (13.2 g). ¹H-NMR: 9.16 (s, 1H), 7.65 (s, 1H), 4.51 (m, 1H),1.47 (d, 6H).

Example 905 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester

A solution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester(3.0 g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol)in MeOH (60 mL) was heated at 80° C. for 4 h. After cooling, the mixturewas filtered and washed with cold MeOH to afford the title compound (2.0g, 71%). ¹H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H).

Example 906 4-(4-Cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine

4-cyclopropyl-5-pyridin-4-yl-2,4-dihydro-3H-1,2,4-triazole-3-thione(11.11 g, 51 mmol) was slowly added to wet Raney nickel (90 g) in EtOH(200 mL) in portions. The reaction mixture was heated at 60° C. for 3.5h and then filtered through celite. The filtrate was concentrated togive the title compound (6.85 g, 72.3%). ¹H-NMR: 8.76 (d, 2H), 8.71 (s,1H), 7.95 (d, 2H), 3.75 (m, 1H), 1.08 (m, 2H) and 0.94 (m, 2H).

Example 907 N-cyclopropylpropanamide

A solution of propionic anhydride (6.41 ml, 50.0 mmol) andcyclopropylamine (3.48 ml, 50.0 mmol) in benzene (50 ml) was heated toreflux for 6 h and then the solvent was evaporated. Recrystallizationfrom EA/hex. afforded the title compound (1.45 g, 26%). ¹H NMR: 0.48 (m,2H) 0.76 (m, 2H) 1.13 (t, 3H) 2.14 (q, 2H) 2.69 (m, 1H)

Example 908 4-(3-Chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester

Sodium hydride (60% oil dispersion, 1.24 g, 31.1 mmol) was added inportions to a solution of 3-chloroacetophenone (4.0 g, 25.9 mmol) anddiethyl oxalate (4.54 g, 31.1 mmol) in DMF (32 mL) at 0° C. The mixturewas stirred at r.t for 1 h and was then heated at 80° C. for 0.5 h.After cooling, the mixture was treated with 3N HCl and then diluted withEA. The organic layer was washed with water and saturated brine, dried(Na₂SO₄), filtered and concentrated. The resulting residue was thenpurified by column chromatography using 0-10% EA in hex to afford thetitle compound (4.43 g, 67%). ¹H NMR: 15.12 (br s, 1H), 7.98 (s, 1H),7.88 (d, 1H), 7.58 (d, 1H), 7.47 (t, 1H), 7.05 (s, 1H), 4.39 (m, 2H),1.41 (m, 3H).

Example 909 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol

27.2 g crude N′-[(3-chlorobenzoyl)oxy]-2-hydroxypropanimidamide wasdissolved in ethanol (250 mL) and refluxed for 1 h, followed by additionof 14.0 g (170 mmol) sodium acetate in water (40 mL). After refluxingo.n., cooling to r.t. and addition of water (250 mL) the mixture wasconcentrated in vacuo to about ½ of its volume, resulting in aprecipitate which was filtered off and recrystallized from EA/Hep toyield 6.45 g (25%) of the title compound. ¹H NMR: 8.14 (s, 1H), 8.02 (d,1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04-5.14 (m, 1H), 2.51 (d, 1H), 1.67(d, 3H)

Example 910 1-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethanol

The title compound was synthesized analogous to1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol. ¹H-NMR: 8.12 (dd,1H), 7.49-7.58 (m, 1H), 7.18-7.27 (m, 1H), 5.12 (q, 1H), 1.68 (d, 3H)

Example 911 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propan-1-ol

Propionaldehyde cyanohydrin (9.62 g, 113 mmol) was added slowly tohydroxylamine (100 ml, 1.27 M in EtOH) at 0° C. Stirring was continuedat r.t. for 3 h and then the reaction mixture was concentrated todryness under reduced pressure to give crude(E/Z)-N′,2-dihydroxybutanimidamide (9.1 g, 68%). Crude(E/Z)-N′,2-dihydroxybutanimidamide (8.0 g, 67.7 mmol) was dissolved inpyridine (350 ml) and 3-chlorobenzoyl chloride (8.72 ml, 67.7 mmol) wasadded slowly at 0° C. After stirring at r.t. for 1 h the mixture washeated at reflux o.n. After cooling to r.t. sat. aq. NaHCO₃ was addedand the mixture was extracted with DCM. The organic phase was washedwith water and brine, dried and concentrated. Column chromatography(hep/EA 4:1) gave 7.15 g (44%) of the title compound. ¹H NMR: 1.04 (t,3H) 2.00 (m, 2H) 2.35 (m, 1H) 4.87 (m, 1H) 7.47 (t, 1H) 7.57 (m, 1H)8.02 (m, 1H) 8.14 (m, 1H)

Example 912 (+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol

A solution of 1.53 g (18.6 mmol) sodium acetate in water (12 mL) wasadded to 3.88 g (16.0 mmol)3-chloro-N′-{[(2R)-2-hydroxypropanoyl]oxy}benzenecarboximidamidedissolved in ethanol (50 mL). The mixture was heated to 90° C. for 5.5 hand then evaporated to dryness and purified via flash chromatography(Hep/EA=9/1) to give after drying 2.3 g (65%) of the title compound. ¹HNMR: 8.09 (t, 1H), 7.97 (td, 1H), 7.45-7.51 (m, 1H), 7.42 (t, 1H), 5.15(qd, 1H), 2.57 (d, 1H), 1.72 (d, 3H)

Example 913 3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]benzonitrile

Hydroxylamine (50% aq., 5.7 g, 172 mmol) was added drop-wise to asolution of hydroxyacetonitrile (55% aq., 8.9 g, 156 mmol) in water (100ml) and stirred at rt for 4 h. Water was evaporated and the residue wasdissolved in EtOH and dried (Na₂SO₄). 3-Cyanobenzoyl chloride (9.5 g,57.1 mmol) in THF (10 ml) was added drop-wise to a slurry of theobtained crude (1E)-N′,2-dihydroxyethanimidamide (4.7 g, 51.9 mmol) andDEA (8.0 g, 62.3 mmol) in THF (10 ml) at 0° C. The reaction mixture wasstirred at 0° C. for 2 h, diluted with Et₂O (100 ml) and washed (NH₄Claq.). The water phase was extracted with Et₂O and the organic layerswere dried (Na2_(S)O₄). The obtained crude(1E)-N′-[(3-cyanobenzoyl)oxy]-2-hydroxyethanimidamide (5.0 g, 22.8 mmol)was dissolved in EtOH (50 ml). NaOAc (2.8 g, 34.2 mmol) was added andthe mixture was refluxed o.n. The reaction mixture was concentrated andthe precipitate recrystallized from EtOH (10 ml) to give the titlecompound (1.4 g). ¹H NMR (DMSO-d6): 8.51 (m, 1H), 8.39 (m, 1H), 8.16 (m,1H), 7.84 (t, 1H), 5.78 (t, 1H), 4.63 (t, 2H).

Example 914 (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol

7.13 g (26.7 mmol)(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate and2.33 g (56.7 mmol) lithium hydroxide monohydrate were mixed with 1:1THF/Water (100 mL) and stirred for 18 h. Reducing the volume of themixture in vacuo to about ½, followed by dilution with brine andextraction with ethyl acetate. 5.8 g (97%) of the title compound wasobtained after evaporation and drying. ¹H NMR: 8.14 (s, 1H), 8.02 (d,1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04-5.14 (m, 1H), 2.42 (br s, 1H),1.67 (d, 3H)

Example 915 (+)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propan-1-ol

The title compound was synthesized analogous to(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol and wasused directly in the next step for(+)-4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine.

Example 916 (−)-(1S)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol

The title compound was isolated from the reaction as described for thesynthesis of (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethylacetate. Isolation took place during DCM elution of the columnchromatography, yielding 5 g (50%) of the title compound. ¹H NMR: 8.14(s, 1H), 8.02 (d, 1H), 7.57 (d, 1H), 7.47 (t, 1H), 5.04-5.14 (m, 1H),2.51 (d, 1H), 1.67 (d, 3H).

Example 917 [5-(3-Chloro-phenyl)-isoxazol-3-yl]-methanol

Lithium aluminum hydride (320 mg, 8.4 mmol) was slowly added to asolution of 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid ethyl ester(2.0 g, 8.4) in THF (100 ml) at r.t After 1 h, the reaction mixture wasquenched with water and then extracted with EA. The organic layer waswashed with water and brine, dried (Na₂SO₄), filtered, and concentrated.The resulting residue was then purified by column chromatography using15-40% EA in hex. to afford the title compound (1.32 g, 75%,). ¹H NMR:7.78 (s, 1H), 7.68 (m, 1H), 7.43 (m, 2H), 6.63 (s, 1H), 4.84 (d, 2H),2.23 (t, 1H).

Example 918 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol

Step 1: 5-(3-Chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester: Asolution of 4-(3-chloro-phenyl)-2,4-dioxo-butyric acid ethyl ester (3.0g, 11.8 mmol) and hydroxylamine hydrochloride (2.46 g, 35.4 mmol) inMeOH (60 ml) was heated at 80° C. for 4 h. After cooling, the mixturewas filtered and washed with cold methanol to afford5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (2.0 g,71%). ¹H NMR: 7.82 (s, 1H), 7.72 (m, 1H), 7.47 (m, 2H), 4.03 (s, 3H).Step 2: 1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanone: In a screw capvial equipped with stir bar was mixed methyl magnesium iodide (3M inEt₂O) (0.79 ml, 2.38 mmol), toluene (1 ml), tetrahydrofuran (0.39 ml,4.77 mmol) and TEA (1 ml, 7.15 mmol). After cooling to 0° C. a solutionof 5-(3-chloro-phenyl)-isoxazole-3-carboxylic acid methyl ester (300 mg,1.19 mmol) in toluene (5 ml) was added, followed by stirring at 0° C.for 5 h. The mixture was then quenched with aq 1N HCl (6.5 ml, 6.5mmol), diluted with toluene (35 ml), sequentially washed with water,sat. aq. sodium bicarbonate, water and brine. The organic phase wasconcentrated in-vacuo. The isolated residue was dissolved in MeOH (8 ml)and 20% aq. KOH (1 ml) was added, followed by stirring at 45° C. for 30min and then concentrated in-vacuo. The residue was dissolved in toluene(60 ml), sequentially washed with water, sat. aq. sodium bicarbonate andwater. The organic phase was concentrated in-vacuo. The crude residuewas purified on silica gel using 2% EA in hex. to isolate the desiredcompound (156 mg, 60%). ¹H-NMR: 7.77 (m, 1H), 7.66 (m, 1H), 7.42 (m,2H), 6.90 (s, 1H), 2.69 (s, 3H). Step 3:1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethanol: In a screw cap vialequipped with stir bar was mixed1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanone (100 mg, 0.45 mmol),sodium borohydride (34 mg, 0.90 mmol) and MeOH (3 ml), followed bystirring at r.t for 3 h and the quenched with water and brine, extractedwith DCM. The combined organic phase was dried (Na₂SO₄), filtered andconcentrated in-vacuo to isolate the title compound. ¹H-NMR: 7.69 (m,1H), 7.59 (m, 1H), 7.37 (m, 2H), 6.59 (s, 1H), 5.07 (q, 1H), 3.45 (br.s, 1H), 1.58 (d, 3H).

Example 919 (+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethylacetate

12.1 g (53.9 mmol) 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanoland 1.60 g Novozyme 435® are taken up under Ar in toluene (750 mL).After addition of 5.0 mL (54.2 mmol) vinyl acetate the reaction was runat r.t. o.n., followed by filtration over celite and washing with DCM.The filtrate was purified over silica using DCM neat, followed byEA/Hep=1/1, yielding 7.1 g (49%) of the title compound. ¹H NMR: 8.13 (t,1H), 8.01 (d, 1H), 7.55 (d, 1H), 7.47 (t, 1H), 6.07 (q, 1H), 2.15 (s,3H), 1.69 (d, 3H)

Example 920 (+)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]propylacetate

The title compound was prepared analogous to(+)-(1R)-1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl acetate withstirring at 70° C. for 6 h. ¹H NMR: 1.00 (t, 3H) 2.07 (m, 2H) 2.16 (s,3H) 5.90 (t, 1H) 7.46 (t, 1H) 7.52-7.59 (m, 1H) 7.98-8.06 (m, 1H) 8.13(t, 1H)

Example 921 3-(1-chloroethyl)-5-(3-chlorophenyl)-[1,2,4]oxadiazole

5 drops of DMF were added to1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethanol (12.3 g, 54.9 mmol)in SOCl₂ (150 mL) and the reaction was heated at 70° C. for 5 h. Theexcess SOCl₂ was evaporated and the residue was purified by columnchromatography (Hep 100% to Hep/EA=5/1) to give 12.4 g (93%) of thetitle compound. ¹H NMR: 1.96 (d, 3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m,1H) 8.04 (m, 1H) 8.17 (t, 1H)

The following examples were synthesized in a manner analogous to thatfor 3-(1-chloroethyl)-5-(3-chlorophenyl)-[1,2,4]oxadiazole. StructureName ¹H-NMR Example No.

5-(5-Chloro-2- fluoro-phenyl)- 3-chloromethyl- [1,2,4]oxadiazole 8.16(m, 1 H), 7.58 (m, 1 H), 7.29 (m, 1 H), 4.72 (s, 3 H). 922

3-Chloromethyl- 5-(3-methyl- phenyl)- [1,2,4]oxadiazole

Example 924 5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole

1.80 g 3-chloro-N′-hydroxybenzenecarboximidamide and 3.7 mL DEA weredissolved under Ar in DCM (100 mL) and cooled on an ice/water bath,followed by addition of 2-chloropropanoyl chloride. After 1 h at r.t.the mixture was concentrated and the crude taken up in DMF (120 mL),followed by heating for at 120° C. for 2 h. The mixture was concentratedonto celite and purified via column chromatography (hep 100% tohep/EA=7/3) yielding the title compound (1.72 g, 67%). ¹H NMR: 8.09 (t,1H), 7.93-8.02 (m, 1H), 7.38-7.54 (m, 2H), 5.22 (q, 1H), 2.02 (d, 3H)

Example 925 5-Chloromethyl-3-(3-chloro-phenyl)-[1,2,4]oxadiazole

The title compound was prepared analogous to5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole. ¹H NMR: 8.07 (t,1H), 7.93-7.98 (m, 1H), 7.46-7.52 (m, 1H), 7.42 (t, 1H), 4.74 (s, 2H)

Example 926 3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile

The title compound was prepared analogous to5-(1-chloroethyl)-3-(3-chlorophenyl)-[1,2,4]oxadiazole. ¹H NMR: 8.40 (s,1H), 8.32 (d, 1H), 7.82 (d, 1H), 7.64 (t, 1H), 4.77 (s, 2H).

Example 927 3-(1-chloro-ethyl)-5-m-tolyl-[1,2,4]oxadiazole

2-Chloro-N-hydroxy-propionamidine (218 mg, 1.78 mmol) and triethylamine(0.677 ml, 4.86 mmol) were added to 3-methyl-benzoyl chloride (250 mg,1.62 mmol) in DCM (10.0 ml) at 0° C. and the resulting mixture wasstirred for 20 min. The solution was concentrated and DMF (20 ml) wasadded to the residue and heated at 120° C. for 20 min. The product waspurified by flash chromatography using 10-20% EA in hex. affording 0.250g (59% yield over 2 steps) of the title compound. GCMS (M/Z)=222.

Example 928 3-Chloromethyl-5-(3-chloro-phenyl)-[1,2,4]oxadiazole

Step A. The acyclic intermediate was obtained from 3-chlorobenzoic acid(2.82 g, 18 mmol), EDCI (3.46 g, 18 mmol), HOBt (2.76 g, 18 mmol) and2-chloro-N-hydroxy-acetamidine (1.75 g, 16.2 mmol) [Chem. Ber. 1907, 40,1639] in DMF (40 mL). Step B: The cyclic compound was obtained fromheating in DMF (40 mL) and purified by SPE chromatography on silica gelusing 2% acetone in hex. yielding the title compound (1.46 g, 39% yieldover 2 steps). ¹H NMR: 8.17 (m, 1H), 8.07 (dd, 1H), 7.60 (m, 1H), 7.55(t, 1H), 4.69 (s, 2H).

Example 929 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile

N′-(chloroacetyl)-3-cyanobenzohydrazide (795 mg, 3.34 mmol) and P₂O₅(4.7 g, 33.4 mmol) were added to DMF (6 ml) and toluene (4 ml). Thereaction mixture was refluxed for 2 h. K₂CO₃ (aq., sat.) was added untilpH was basic and the mixture was extracted with DCM. The combinedorganic layers were dried (Na₂SO₄) and purified with flashchromatography using 0 to 100% EA in hep. to give the title compound(209 mg, 29%). ¹H NMR: 8.29 (m, 2H), 7.82 (m, 1H), 7.66 (t, 1H), 4.78(s, 2H).

Example 930 3-cyanobenzohydrazide

3-cyanobenzoyl chloride (4.8 g, 29.0 mmol) was dissolved in DCM (20 ml)and MeOH (40 ml) was added in portions at 0° C. The mixture was stirredat 0° C. for 1 h and at rt for 2 h. The solvents were evaporated and thecrude methyl ester was dissolved in EtOH (50 ml) and hydrazine (24% aq.,9 ml, 45 mmol) was added. The reaction mixture was refluxed for 48 h andthe solvents were evaporated (coevaporation with water). The residue waspurified with prep. HPLC to give the title compound (1.8 g, 39%). ¹H NMR(DMSO-d6): 9.98 (br s, 1H), 8.21 (m, 1H), 8.13 (m, 1H), 7.99 (m, 1H),7.69 (t, 1H), 4.61 (br s, 2H).

Example 931 N′-(chloroacetyl)-3-cyanobenzohydrazide

3-cyanobenzohydrazide (1.6 g, 10.0 mmol) was added to THF (40 ml) andDMF (10 ml). TEA (1.4 ml, 10.0 mmol) was added at 0° C. followed bychloroacetyl chloride (1.0 ml, 12.6 mmol) and the reaction mixture wasstirred at 0° C. for 1 h and at rt for 2 h. The THF was evaporated,water was added to the remaining mixture, followed by filtration overcelite and purification with prep. HPLC to give the title compound (1.6g, 69%). ¹H NMR (DMSO-d6): 10.62 (br s, 2H), 8.28 (m, 1H), 8.18 (m, 1H),8.08 (m, 1H), 7.75 (t, 1H), 4.22 (s, 2H).

Example 932 3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole

3-(chloromethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (1.38 g, 6.0 mmol)and LiBr (0.90 g, 10.3 mmol) in THF (50 ml) were heated to reflux undera nitrogen atm. o.n. After cooling to r.t. EA was added and the organicphase was washed with H₂O and brine, dried and evaporated to give thetitle compound (1.40 g, 85%). MS (M⁺+1) 275.

Example 933 3-(bromomethyl)-5-(3-methylphenyl)-1,2,4-oxadiazole

The title compound was prepared analogous to3-(bromomethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole MS (M⁺+1) 253.

Example 934 3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole

A solution of NBS (396 mg, 2.22 mmol) in THF (2 ml) was added dropwiseto a solution of triphenylphosphine (583 mg, 2.22 mmol) in THF (2 ml) at0° C. After stirring for 20 min1-[5-(3-chloro-phenyl)-1,2,4-oxadiazol-3-yl]-ethanol (416 mg, 1.85 mmol)in THF (2 ml) was added. Stirring was continued o.n. at r.t. before thesolvent was removed under reduced pressure. Flash chromatography (hep/EA6:1) afforded 168 mg (32%) of the title compound. ¹H NMR: 2.12 (d, 3H)5.21 (q, 1H) 7.47 (t, 1H) 7.57 (m, 1H) 8.03 (d, 1H) 8.15 (s, 1H)

Example 9363-(1-bromoethyl)-5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazole

1.6 g 1-[5-(5-chloro-2-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethanol wasdissolved in benzene (30 mL), followed by addition of 0.6 mL phosphoroustribromide. After heating to reflux for 90 min water (15 mL) was added.Solid NaHCO₃ was added, followed by extraction with CHCl₃. After dryingover Na₂SO₄ and removal of solvent, purification was done on 2 mmchromatotron plate (hep 100% to hep/EA=99/1) to yield 0.60 g (32%) ofthe title compound. ¹H NMR: 8.15 (dd, 1H), 7.49-7.59 (m, 1H), 7.19-7.26(m, 1H), 5.23 (q, 1H), 2.13 (d, 3H)

Example 937 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethylmethanesulfonate

Methane sulfonyl chloride (40 ml, 0.49 mmol) was added to a mixture ofTEA (95 ml, 0.67 mmol) and1-[5-(3-Chloro-phenyl)-1,2,4-oxadiazol-3-yl]-ethanol (100 mg, 0.45 mmol)in DCM (5 ml). After stirring for 15 min the mixture was washed withwater and brine, dried and concentrated to yield the title compound (135mg). ¹H NMR: 1.9 (d, 3H) 3.1 (s, 3H) 5.9 (q, 1H) 7.5 (t, 1H) 7.6 (m, 1H)8.0 (m, 1H) 8.1 (t, 1H)

The following examples were synthesized in a manner analogous to thatfor 1-[5-(3-chlorophenyl)-[1,2,4]oxadiazol-3-yl]ethyl methanesulfonate.Structure Name ¹H-NMR Example No.

[5-(3- chlorophenyl)- isoxazol-3- yl]methyl methanesulfonate 7.80 (s, 1H), 7.70 (m, 1 H) 7.45 (m, 2 H), 6.73 (s, 1 H), 5.37 (s, 2 H), 3.16 (s,3 H). 938

[5-(3- cyanophenyl)- 1,2,4- oxadiazol-3- yl]methyl methanesulfonate

Example 940 5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine

Hydroxycarbonimidic dibromide (2.21 g, 10.89 mmol) was added portionwiseover 1 h 20 min to a mixture of 3-chlorobenzonitrile (3.00 g, 21.29mmol) and NaHCO₃ (2.9 g, 34.87 mmol) in toluene (3 ml) at 90° C.Stirring was continued for 3 h and then the reaction mixture was cooledto r.t., diluted with EA and washed with water. The organic phase wasdried and concentrated. A mixture of 3-chlorobenzonitrile and3-bromo-5-(3-chlorophenyl)-1,2,4-oxadiazole was obtained after flashchromatography (hex/EA 10:1). 1.0 g of the mixture was dissolved inMeNH₂ (4 ml, 8.5 M in EtOH) and heated in a microwave reactor for 30 minat 60° C. The volatiles were removed under reduced pressure and theresidue was dissolved in water and extracted with CHCl₃. The organicphase was dried and concentrated. Recrystallization from EA gave 137 mgof the title compound. ¹H NMR: 3.00 (d, 3H) 4.35 (bs, 1H) 7.43 (t, 1H)7.50-7.55 (m, 1H) 7.92 (d, 1H) 8.03 (s, 1H)

Example 941 5-(3-chlorophenyl)-N-ethyl-1,2,4-oxadiazol-3-amine

The title compound was prepared analogous to5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine. ¹H NMR: 1.28 (t,3H) 3.36 (q, 2H) 7.43 (t, 1H) 7.49-7.55 (m, 1H) 7.92 (m, 1H) 8.03 (s,1H)

Example 942 4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine

Sulfuryl dichloride (0.58 ml, 8.34 mmol) in DCM (8 ml) was slowly addedto a cooled (−10° C.) solution of4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridine (454 mg, 2.61 mmol) inDCM (25 ml) and DMF (8 ml) and then the solution was stirred for 2 h.NaHCO3 (sat.) was added and the mixture was extracted with EA. Theorganic phase was dried and concentrated. Recrystallization from EAafforded 124 mg (23%) of the title compound. ¹H NMR: 3.83 (s, 3H) 4.84(s, 2H) 7.62 (d, 2H) 8.82 (d, 2H).

Preparation of Final Compounds

Example 9434-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine

n-BuLi (210 ml, 2.5 M in hex., 0.52 mmol) was added dropwise to asolution of 4-(4-cyclopropyl-5-methyl-4H-1,2,4-triazol-3-yl)pyridine (80mg, 0.4 mmol) in THF (10 ml) at −78° C. under an atm. of nitrogen. Afterstirring for 15 min3-(1-Bromo-ethyl)-5-(3-chloro-phenyl)-[1,2,4]oxadiazole (115 mg, 0.4mmol) in THF (2 ml) was added. The mixture was stirred for 2 h at −78°C. and then at r.t. for 1 h. The solvent was removed under reducedpressure and the desired product was obtained by prep. HPLC in 20 mgyield. ¹H NMR: 0.7 (m, 2H) 1.2 (ddd, 2H) 1.6 (d, 3H) 3.2 (dd, 1H) 3.3(ddd, 1H) 3.6 (dd, 1H) 3.9 (m, 1H) 7.5 (t, 1H) 7.6 (m, 1H) 7.7 (m, 2H)8.0 (m, 1H) 8.1 (t, 1H) 8.7 (m, 2H)

The following examples were synthesized in a manner analogous to thatfor4-(5-{2-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine.Example Structure No. Name ¹H-NMR

944 4-(5-{2-[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]ethyl}-4-cyclopropyl-4 H- 1,2,4-triazol-3- yl)pyridine 0.72-0.78 (m, 2 H) 1.21(m, 2 H) 3.35 (m, 1 H) 3.41-3.48 (m, 2 H) 3.49-3.57 (m, 2 H) 7.47 (m, 1H) 7.53- 7.59 (m, 1 H) 7.73 (m, 2 H) 7.95-8.03 (m, 1 H) 8.11 (tm, 1 H)8.76 (d, 2 H).

945 4-(5-{2-[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]-1-methylethyl}-4- cyclopropyl-4 H- 1,2,4-triazol-3- yl)pyridine 0.62-0.72(m, 1 H) 0.81-0.92 (m, 1 H) 1.14-1.21 (m, 2 H) 1.52 (d, 3 H) 3.24 (m, 1H) 3.35 (m, 1 H) 3.56 (m, 1 H) 3.83-3.93 (m, 1 H) 7.41 (t, 1 H) 7.50 (m,1 H) 7.68 # (d, 2 H) 7.91 (d, 1 H) 8.01 (t, 1 H) 8.70 (d, 2 H)

946 4-(5-{2-[5-(5- chloro-2- fluorophenyl)- 1,2,4-oxadiazol-3-yl]propyl}-4- methyl-4 H- 1,2,4-triazol-3- yl)pyridine 1.58 (d, 3 H)3.17 (m, 1 H) 3.8 (m, 1 H) 3.72 (s, 3 H) 3.82-3.93 (m, 1 H) 7.20 (t, 1H) 7.52 (m, 1 H) 7.59 (d, 2 H) 8.07 (m, 1 H) 8.77 (s, 2 H)

947 4-(5-{2-[5-(5- chloro-2- fluorophenyl)- 1,2,4-oxadiazol-3-yl]propyl}-4- cyclopropyl-4 H- 1,2,4-triazol-3- yl)pyridine 0.69-0.81(m, 2 H) 1.15-1.27 (m, 2 H) 1.59 (d, 3 H) 3.23 (m, 1 H) 3.38 (m, 1 H)3.57 (m, 1 H) 3.92-4.03 (m, 1 H) 7.20 (t, J = 9.35 Hz, 1 H) 7.52 (m, 1H) # 7.77 (d, 2 H) 8.07 (m, 1 H) 8.76 (d, 2 H)

948 4-(4-methyl-5- {2-[5-(3- methylphenyl)- 1,2,4-oxadiazol-3-yl]ethyl}-4 H- 1,2,4-triazol-3- yl)pyridine 2.41 (s, 3 H) 3.28 3.37(m, 2 H) 3.44- 3.52 (m, 2 H) 3.72 (s, 3 H) 7.38 (m, 2 H) 7.61 (d, 2 H)7.85-7.90 (m, 1 H) 7.90 (s, 1 H) 8.78 (bs, 2 H)

949 4-(4- cyclopropyl-5- {1-methyl-2-[5- (3- methylphenyl)-1,2,4-oxadiazol- 3-yl]ethyl}-4 H- 1,2,4-triazol-3- yl)pyridine 0.69 (m,1 H) 0.87 (m, 1 H) 1.14-1.24 (m, 2 H) 1.55 (d, 3 H) 2.40 H) 1.55 (d, 3H) 2.40 (s, 3 H) 3.26 (m, 1 H) 3.35 (m, 1 H) 3.57 (m, 1 H) 3.85-3.95 #(m, 1 H) 3.85-3.95 (m, 1 H) 7.37 (d, 2 H) 7.73 (m, 2 H) 7.81-7.89 (m, 2H) 8.73 (bs, 2 H)

Example 9503-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-ethyl}-[1,2,4]oxadiazole

3-chloro-N′-hydroxybenzenecarboximidamide (54.3 mg, 0.32 mmol),3-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-propionicacidethyl ester (100 mg, 0.32 mmol) and sodium-tert-butoxide (30.6 mg,0.32 mmol) were mixed with EtOH (1 ml) and toluene (1 ml), followed bystirring at 100° C. for 24 h. The mixture was then concentrated,in-vacuo, and the residue was purified via column chromatography using50% EA in hex. and then triturated with Et₂O to isolate the titlecompound (27 mg). ¹H-NMR: 8.1 (m, 1H), 7.97 (dd, 1H), 7.64 (d, 2H), 7.47(m, 2H), 6.96 (d, 2H), 6.88 (s, 1H), 3.87 (s, 3H), 3.37 (m, 4H), 3.24(m, 1H), 1.06 (m, 2H), 0.68 (m, 2H).

Example 9513-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole

The title compound was synthesized analogous to3-(3-Chloro-phenyl)-5-{2-[3-cyclopropyl-2-(4-methoxy-phenyl)-3H-imidazol-4-yl]-ethyl}-[1,2,4]oxadiazole.¹H-NMR: 8.1 (m, 1H), 7.98 (dd, 1H), 7.63 (d, 2H), 7.46 (m, 2H), 6.97 (d,2H), 6.85 (s, 1H), 3.88 (s, 3H), 3.65 (m, 1H), 3.42 (m, 1H), 3.15 (m,2H), 1.58 (d, 3H), 1.06 (m, 2H), 0.67 (m, 2H).

Example 9524-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl-1H-imidazol-2-yl)-pyridine

3-chloro-N-hydroxy-benzamidine (486 mg, 2.85 mmol),3-(3-cyclopropyl-2-pyridin-4-yl-3H-imidazol-4-yl)-2-methyl-propionicacid (702 mg, 2.59 mmol), EDCI (546 mg, 2.85 mmol) and HOBt hydrate (385mg, 2.85 mmol) were mixed with DMF (20 ml) and stirred o.n. at r.t. Thereaction was diluted with water and extracted with EA. The combinedorganic phase was successively washed with sat. aq. sodium bicarbonate,brine, dried (Na₂SO₄), filtered and concentrated in-vacuo. The residuewas heated in DMF (10 ml) at 120° C. for 2 h. The reaction mixture wascooled to r.t., diluted with EA (50 ml), successively washed with waterand brine, dried (Na₂SO₄), filtered and concentrated in-vacuo. The crudewas purified via column chromatography using 2% MeOH in DCM to isolatethe title compound (404 mg). ¹H-NMR: 8.69 (dd, 2H), 8.09 (m, 1H), 7.96(d, 1H), 7.67 (dd, 2H), 7.46 (m, 2H), 6.94 (s, 1H), 3.66 (m, 1H), 3.48(m, 1H), 3.31 (m, 1H), 3.16 (m, 1H), 1.59 (d, 3H), 1.19 (m, 2H), 0.72(m, 2H).

Example 9533-(3-Chloro-phenyl)-5-{2-[2-(4-methoxy-phenyl)-3-methyl-3H-imidazol-4-yl]-1-methyl-ethyl}-[1,2,4]oxadiazole

The title compound was synthesized analogous to4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-1-cyclopropyl-1H-imidazol-2-yl)-pyridine.¹H-NMR: 8.1 (m, 1H), 7.98 (dd, 1H), 7.50 (m, 4H), 6.97 (d, 2H), 6.92 (s,1H), 3.87 (s, 3H), 3.62 (s, 3H) 3.54 (m, 1H), 3.30 (m, 1H), 3.00 (m,1H), 1.57 (d, 3H).

Example 954(S)-4-(5-{2-[3-(3-Chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine

After 3-chloro-N-hydroxy-benzamidine (0.7 g, 4.1 mmol) was mixed withpotassium-tert-butoxide (0.373 g, 3.33 mmol) in n-propanol at 80° C. for10 min,3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionicacid ethyl ester (1.0 g, 3.33 mmol) was added to the reaction mixtureand heated at 100° C. for 3 h. The reaction mixture was concentrated,quenched with sat. ammonium chloride and extracted with DCM. The organiclayer was dried with MgSO₄, purified by column chromatography andtriturated with Et₂O to give racemic4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H-[1,2,4]triazol-3-yl)-pyridine(0.8 g, 59%). The title product (10 mg) was obtained by separation onChiracel OJ with EtOH:hex. (1:4). ¹H-NMR: 8.78 (d, 2H), 8.05 (s, 1H),7.96 (d, 1H), 7.74 (d, 2H), 7.50 (d, 1H), 7.43 (t, 1H), 4.15 (m, 1H),3.64 (dd, 1H), 3.31 (m, 2H), 1.67 (d, 3H), 1.25 (m, 2H) and 0.78 (m,2H).

Example 9554-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine

3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionicacid ethyl ester (2.14 g, 7.1 mmol) was mixed with hydrazine monohydratein ethanol at 120° C. in a sealed flask for 2 hours. The reactionmixture was concentrated and triturated with ether to give3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionicacid hydrazide. This compound was mixed with 3-Chloro-benzimidic acidethyl ester hydrochloride (0.722 g, 7.8 mmol) in ethanol at 130° C. o.n.The reaction mixture was concentrated, quenched with saturated sodiumcarbonate, extracted with DCM. The organic layer was dried and purifiedby column chromatograph with 5% methanol (2M NH₃) in DCM to racemic4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H[1,2,4]triazol-3-yl)-pyridine1.19 g (41.1%). This material (70 mg) was separated on Chiralpak ADusing ethanol as eluent to give the title compound. ¹H-NMR: 8.77 (d,2H), 8.02 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.51 (d, 1H), 7.47 (t,1H), 4.12 (m, 1H), 3.69 (dd, 1H), 3.44 (m, 1H), 3.26 (dd, 1H), 1.66 (d,3H), 1.24 (m, 2H) and 0.79 (m, 2H).

Example 9564-(5-{(2R)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine

The title compound was obtained from chiral LC separation in example4-(5-{(2S)-2-[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]propyl}-4-cyclopropyl-4H-1,2,4-triazol-3-yl)pyridine.

Example 9574-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine

1.45 g (6.08 mmol)4-[4-Methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine, 1.73 g(7.70 mmol) 1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol and 4.03g (12.3 mmol) cesium carbonate were dissolved under Ar-atmosphere in DMF(25 mL) and stirred at 30° C. for 3 d. After filtration and evaporationto dryness the crude was purified on 4 mm silica chromatotron plate(DCM/MeOH=100/0 to 90/10). Further purification on 2 mm silicachromatotron plate (Hep/EA/MeOH=15/15/1) gave 0.36 g (15%) of the titlecompound. ¹H NMR: 8.75 (br s, 2H), 8.12 (s, 1H), 8.00 (d, 1H), 7.64 (d,2H), 7.56 (d, 1H), 7.46 (t, 1H), 6.39 (q, 1H), 3.63 (s, 3H), 1.94 (d,3H).

The following examples were synthesized analogous to4-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine.Example Structure No. Name ¹H-NMR

958 5-(3- chlorophenyl)-3- ((1R)-1-{[4- methyl-5- (trifluoromethyl)- 4H-1,2,4-triazol- 3-yl]oxy}ethyl)- 1,2,4-oxadiazole 8.13 (m, 1 H) 8.01(m, 1 H) 7.58 (m, 1 H) 7.48 (m, 1 H) 6.24 (q, 1 H) 3.74 (s, 3 H) 1.90(d, 3 H).

959 3-(5-{1-[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]ethoxy}-4-cylcopropyl-4 H- 1,2,4-triazol-3- yl)pyridine 1.04 (m, 4 H) 1.96 (d, 3H) 3.21 (m, 1 H) 6.41 (q, 1 H) 7.45 (m, 2 H) 7.58 (m, 1 H) 8.03 (d, 1 H)8.15 (m, 2 H) 8.70 (bd, 1 H) 9.08 (bs, 1 H)

960 3-(5-{(1R)-1-[5- (3-chlrophenyl)- 1,2,4-oxadiazol- 3-yl]ethoxy}-4-methyl-4 H-1,2,4- triazol-3- yl)pyridine 1.95 (d, 3 H) 3.59 (s, 3 H)6.39 (q, 1 H) 7.46 (m, 1 H) 7.49 (t, 1 H) 7.58 (m, 1 H) 8.02 (m, 2 H)8.14 (t, 1 H) 8.72 (bd, 1 H) 8.89 (bs, 1 H)

961 5-(3- chlorophenyl)-3- ((1R)-1-}[5-(4- fluorophenyl)-4- methyl-4H-1,2,4- triazol-3- yl]oxy}ethyl)- 1,2,4-oxadiazole 8.14 (m, 1 H) 8.02(m, 1 H) 7.93-7.99 (m, 2 H) 7.57 (m, 1 H) 7.47 (m, 1 H) 7.06 (m, 2 H)6.30 (q, 1 H) 3.71 (s, 3 H) 1.90 (d, 3 H).

962 5-(3- chlorophenyl)-3- ((1R)-1-}[5-(3,5- difluorophenyl)- 4-methyl-4H- 1,2,4-triazol-3- yl]oxy}ethyl)- 1,2,4-oxadiazole 1.93 (d, 3 H) 3.57(s, 3 H) 6.37 (m, 1 H) 6.86-6.97 (m, 1 H) 7.20 (d, 2 H) 7.46 (t, 1 H)7.56 (d, 1 H) 8.00 (d, 1 H) 8.12 (s, 1 H)

963 (+)-4-(5-{1-[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]propoxy}-4-methyl-4 H-1,2,4- triazol-3- yl)pyridine 1.12 (t, 3 H) 2.25-2.36 (m, 2H) 3.64 (s, 3 H) 6.22 (t, J = 6.57 Hz, 1 H) 7.46 (t, 1 H) 7.54-7.63 (m,3 H) 7.97- 8.05 (m, 1 H) 8.12 (t, 1 H) 8.70- # 8.78 (m, 2 H).

964 (−)-4-(5-{(1 R)-1- [5-(3- chlorophenyl)- 1,2,4-oxadiazol-3-yl]ethoxy}-4- methyl-4 H-1,2,4- triazol-3- yl)pyridine 8.74 (d, 2 H),8.13 (t, 1 H), 8.01 (d, 1 H), 7.60 (dd, 2 H), 7.57 (d, 1 H), 7.47 (t, 1H), 6.39 (q, 1 H), 3.63 (s, 3 H), 1.94 (d, 3 H).

965 (+)-4-(5-{(1S)-1- [5-(3- chlorophenyl)- 1,2,4-oxadiazol-3-yl]ethoxy}-4- methyl-4 H-1,2,4- triazol-3- yl)pyridine 8.71 (d, 2 H),8.09 (s, 1 H), 7.97 (d, 1 H), 7.57 (d, 2 H), 7.54 (d, 1 H), 7.44 (t, 1H), 6.36 (q, 1 H), 3.60 (s, 3 H), 1.91 (d, 3 H).

Example 966(−)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine

0.57 g (2.54 mmol)(+)-(1R)-1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethanol, 0.64 g(2.68 mmol)4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine and 0.90 g(2.76 mmol) cesium carbonate were stirred at 65° C. for 6 h, followed bydilution with water. Extraction with EA, washing with aq. citric acid,drying over Na₂SO₄, followed by purification via chromatotron 2 mm(Hep/EA/MeOH=10/10/1) gave 0.81 g (83%) racemic4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine.Prep. chiral separation on Chiralpak AD using 100% 2-propanol yielded0.25 g of the title compound as the second eluting enantiomer. ¹H NMR:8.76 (d, 2H), 8.07 (t, 1H), 7.92-7.99 (m, 1H), 7.60-7.68 (m, 2H),7.45-7.51 (m, 1H), 7.41 (t, 1H), 6.45 (q, 1H), 3.66 (s, 3H), 1.99 (d,3H)

Example 967(+)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine

0.2 g of the title compound was isolated as the first eluting enantiomerduring preparative chiral HPLC separation in the example of(−)-4-(5-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine.¹H NMR: 8.77 (d, 2H), 8.07 (t, 1H), 7.93-8.00 (m, 1H), 7.68 (dd, 2H),7.45-7.52 (m, 1H), 7.41 (t, 1H), 6.45 (q, 1H), 3.67 (s, 3H), 1.99 (d,3H)

Example 9684-(5-{1-[5-(3-Chloro-phenyl)-isoxazol-3-yl]-ethoxy}-4-methyl-4H-[1,2,4]triazol-3-yl)-pyridine

1-[5-(3-chloro-phenyl)-isoxazol-3-yl]-ethanol (63.4 mg, 0.28 mmol), DMFand sodium hydride (60% dispersion in oil, 15.1 mg, 0.38 mmol) weremixed under inert atm. and stirred at r.t for 1 h, followed by additionof 4-[4-methyl-5-(methylsulfonyl)-4H-1,2,4-triazol-3-yl]pyridine (45 mg,0.19 mmol). After stirring at 80° C. for 24 h, the mixture was cooled tor.t., diluted with EA, sequentially washed with water and brine. Theorganic phase was dried (Na₂SO₄), filtered and concentrated, in-vacuo.The crude residue was purified via column chromatography using 5% MeOHin EA to isolate the title compound (11.7 mg). ¹H-NMR: 8.81 (bs, 2H),7.77 (s, 1H), 7.67 (m, 3H), 7.42 (m, 2H), 6.73 (s, 1H), 6.36 (q, 1H),3.62 (s, 3H), 1.94 (d, 3H).

Example 969N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine

NaH (14 mg, 0.35 mmol) was added toN,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine (33 mg, 0.18 mmol)in DMF (3 mL). After 30 min3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (80 mg, 0.18 mmol)in DMF (1 mL) was added to the mixture and the reaction was stirred at60° C. o.n. Brine was added and the mixture was extracted with EA. Theorganic phase was dried and concentrated. The product was purified bycolumn chromatography (DCM to DCM-MeOH 30:1) to give 31 mg (43%) of thetitle compound. ¹H NMR: 1.71 (d, 3H) 2.97 (s, 3H) 3.67 (s, 3H) 4.88 (q,1H) 7.46 (m, 2H) 7.56 (d, 1H) 8.00 (d, 1H) 8.10 (d, 2H) 8.71 (bs, 1H)8.92 (bs, 1H)

The following examples were made in a manner analogous to that forN-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-amine.Example Structure No. Name ¹H-NMR

970 3-Pyridin-4-yl-8-[1-(5-m- tolyl-[1,2,4]oxadiazol-3-yl)-ethyl]-5,6,7,8- tetrahydro- [1,2,4]triazol[4,3- a]pyrimidine 1.76(d, 3 H) 2.18 (m, 2 H) 2.44 (s, 3 H) 3.46 (t, 2 H) 4.15 (m, 2 H) 5.99(q, 2 H) 7.40 (d, 2 H) 7.62 (d, 2 H) 7.89 (d, 1 H) 7.90 (s, 1 H) 8.70(d, 2 H).

971 N,4-dimethyl-N-{[5-(3- methylphenyl)-1,2,4-oxadiazol-3-yl]methyl}-5- pyridin-4-yl-4 H-1,2,4- triazol-3-amine 2.43(s, 3 H) 3.08 (s, 3 H) 3.71 (s, 3 H) 4.56 (s, 2 H) 7.40 (d, 2 H) 7.66(d, 2 H) 7.92 (m, 2 H) 8.77 (bs, 2 H)

972 N-{[5-(5-chloro-2- fluorophenyl)-1,2,4- oxadiazol-3-yl]methyl}-N,4-dimethyl-5-pyridin-4- yl-4 H-1,2,4-triazol-3- amine 3.04 (s, 3 H)3.66 (s, 3 H) 4.56 (s, 2 H) 7.19 (m, 1 H) 7.49 (m, 1 H) 7.64 (bs, 2 H)8.03 (m, 1 H) 8.72 (bs, 2 H)

973 N-{[5-(4-chlorophenyl)- 1,2,4-oxadiazol-3- yl]methyl}-N-cyclopropyl-4-methyl-5-pyridin-4-yl- 4 H-1,2,4-triazol-3-amine 1H NMR: 0.6 (s, 2 H)0.8 (d, 2 H) 3.1 (s, 1 H) 3.7 (s, 3 H) 4.7 (s, 2 H) 7.4 (t, 1 H) 7.5 (d,1 H) 7.6 (d, 2 H) 7.9 (d, 1 H) 8.1 (s, 1 H) 8.7 (s, 2 H)

Example 974(+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine

To a solution of5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.47 g,2.10 mmol) in DMF (10 ml) at r.t. under nitrogen was added NaH (77 mg,3.20 mmol). After stirring for 15 min. a solution of1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl methanesulfonate (0.70g, 2.30 mmol) in DMF 10 ml was added. After 3 h the mixture was dilutedwith sat. NH₄Cl solution and then extracted with EA. The organic phasewas washed with H₂O and brine, dried and evaporated. Purification bysilica gel chromatography using hex.:EA=1:1 afforded 400 mg of theracemicN-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine,which was separated using prep. chiral HPLC on a Chiralpak AD column(hex./2-propanol 80/20 to 100% 2-propanol) to give 183 mg (21%) of thetitle compound which eluted last. ¹H NMR: 1.68 (d, 3H) 2.89 (s, 3H) 3.62(s, 3H) 4.79 (q, 1H) 6.80-6.90 (m, 1H) 7.19 (d, 2H) 7.40 (t, 1H) 7.49(d, 1H) 7.94 (d, 1H) 8.04 (s, 1H)

Example 975(−)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine

186 mg of the title compound was isolated as the first elutingenantiomer during preparative chiral HPLC separation in example of(+)-N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-5-(3,5-difluorophenyl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine.¹H NMR: 1.68 (d, 3H) 2.89 (s, 3H) 3.62 (s, 3H) 4.79 (q, 1H) 6.80-6.90(m, 1H) 7.19 (d, 2H) 7.40 (t, 1H) 7.49 (d, 1H) 7.94 (d, 1H) 8.04 (s,1H).

Example 976(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine

NaH (716 mg, 29.8 mmol) was added slowly to a solution of3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (5.0g, 24.8 mmol) in DMF (250 ml) under nitrogen. After 10 min a solution of3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (6.0 g, 24.8 mmol)in DMF (200 ml) was added, followed by stirring o.n. at r.t. A sat NH₄Clsolution was added followed by water. The mixture was extracted with EAand DCM. The combined organic extracts were washed with water and brine,dried and concentrated. Recrystallization from EA gave 2.24 g (22%) ofthe racemic product8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine.Separation on a Chiralpak AD column (100% 2-propanol) gave the titlecompound which eluted as second enantiomer. ¹H NMR: 1.74 (d, 3H) 2.17(m, 2H) 3.45 (m, 2H) 4.10 (m, 2H) 5.96 (m, 1H) 7.44 (t, 1H) 7.53 (m, 1H)7.59 (m, 2H) 7.97 (m, 1H) 8.08 (m, 1H) 8.67 (d, 2H)

Example 977(−)-8-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine

The title compound was isolated as the first eluting enantiomer duringpreparative chiral HPLC separation in example of(+)-8-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine.¹H NMR: 1.74 (d, 3H) 2.17 (m, 2H) 3.45 (m, 2H) 4.10 (m, 2H) 5.96 (m, 1H)7.44 (t, 1H) 7.53 (m, 1H) 7.59 (m, 2H) 7.97 (m, 1H) 8.08 (m, 1H) 8.67(d, 2H)

Example 978(−)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

Prep. chiral HPLC separation on Chiralpak AD (100% 2-propanol) yieldedthe title compound as the last eluting isomer. ¹H NMR: 8.74 (s, 2H),8.05 (t, 1H), 7.87-8.00 (m, 1H), 7.56-7.69 (m, 2H), 7.32-7.53 (m, 2H),5.03 (q, 1H), 3.68 (s, 3H), 2.98 (s, 3H), 1.81 (d, 3H)

Example 979(+)-N-{1-[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

Prep. chiral HPLC separation on Chiralpak AD (100% 2-propanol) yieldedthe title compound as the first eluting isomer. ¹H NMR: 8.74 (s, 2H),8.05 (t, 1H), 7.87-8.00 (m, 1H), 7.56-7.69 (m, 2H), 7.32-7.53 (m, 2H),5.03 (q, 1H), 3.68 (s, 3H), 2.98 (s, 3H), 1.81 (d, 3H)

Example 980(−)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

Prep. chiral HPLC separation on Chiralpak AD (100% 2-propanol) ofracemicN-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amineyielded the title compound which eluted last.

Example 981(+)-N-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

The title compound was isolated as the first eluting enantiomer duringprep. chiral HPLC separation in example of(−)-N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine.

Example 9823-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl)[1,3,4]oxadiazol-2-yl]benzonitrile

3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (172mg, 0.85 mmol) and 3-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]benzonitrile(94 mg, 0.43 mmol) were dissolved in butanone (5 ml) and K₂CO₃ (118 mg,0.85 mmol) and KI (35 mg, 0.21 mmol) were added. The reaction mixturewas refluxed for 1 h and the solvent was evaporated. The residue wasdissolved in K₂CO₃ (aq., 1M, 25 ml) and was extracted with DCM. Thecombined organic layers were dried (Na₂SO₄) and purified with prep. HPLCto give the title compound (27 mg, 16%). ¹H NMR: 8.75 (d, 2H), 8.30 (m,2H), 7.79 (d, 1H), 7.63 (m, 1H), 7.53 (dd, 2H), 5.57 (d, 2H), 4.06 (t,2H), 3.58 (t, 2H), 1.99 (m, 2H).

The following compounds were prepared analogous to3-[5-(3-Pyridin-4-yl-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl)[1,3,4]oxadiazol-2-yl]benzonitrile Example Structure No. Name ¹H-NMR

983 3-{5-[3-(2-Methoxypyridin- 4-yl)-6,7-dihydro-5 H-[1,2,4]triazolo[4,3- a]pyrimidin-8- ylmethyl][1,3,4]oxadiazol-2-yl}benzonitrile 8.31 (s, 1 H), 8.26 (t, 2 H), 7.80 (d, 1 H), 7.63 (t,1 H), 7.11 (d, 1 H), 6.93 (s, 1 H), 5.48 (d, 2 H), 4.01 (t, 2 H), 3.96(s, 3 H), 3.56 (s, 2 H), 1.96 (s, 2 H).

984 3-(5-{[Methyl-(4-methyl-5- pyridin-4-yl-4 H-[1,2,4]triazol-3-yl)-amino]- methyl}[1,3,4]oxadiazol-2- yl)benzonitrile8.77 (s, 2 H), 8.30 (m, 2 H), 7.82 (d, 1 H), 7.65 (m, 3 H), 4.79 (s, 2H), 3.71 (s, 3 H), 3.11 (s, 3 H).

985 3-{5-[3-(2-Methoxy- pyridin-4-yl)-6,7-dihydro- 5H-[1,2,4]triazolo[4,3- a]pyrimidin-8-ylmethyl]- [1,2,4]oxadiazol-3-yl}-benzonitrile

Example 9863-{3-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-5-yl}benzonitrile

[5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methyl methanesulfonate (0.278g; 0.99 mmol) and3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (0.220g; 1.09 mmol) were dissolved in butanone (20 ml) and potassium carbonate(0.275 g; 1.99 mmol) was added portionwise. The mixture was heated atreflux for 18 h before cooling to r.t. This mixture was concentrated invacuo and DCM (20 ml) was added. The mixture was washed with water,dried (Na₂SO₄), evaporated and purified using prep. HPLC chromatographyto give the title compound (5.4 mg). ¹H NMR: 8.77 (m, 2H), 8.41 (s, 1H),8.34 (d, 1H), 7.87 (d, 1H), 7.68 (t, 1H), 7.56 (m, 2H) 5.51 (s, 2H),4.09 (m, 2H), 3.62 (m, 2H), 2.19 (m, 2H).

Example 9873-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl](methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile

Sodium hydride (0.013 g, 0.53 mmol) was added portionwise to a stirredsolution of5-(2-methoxypyridin-4-yl)-N,4-dimethyl-4H-1,2,4-triazol-3-amine (0.086g; 0.39 mmol) in DMF (10 ml) at 0° C. The mixture was stirred for 30minutes before [5-(3-cyanophenyl)-1,2,4-oxadiazol-3-yl]methylmethanesulfonate (0.1 g; 0.36 mmol) in DMF (1 ml) was added dropwise.The mixture was stirred at r.t. for 3 h before quenching with water (30ml). The resulting mixture was extracted with EA (3×40 ml). The organicswere combined, dried (Na₂SO₄) and evaporated to give a crude material,which was purified by prep. HPLC to give the title compound (0.061 g;42.3%). ¹H NMR: 8.49 (s, 1H), 8.33 (dd, 1H), 8.28 (d, 1H), 7.86 (dd,1H), 7.67 (t, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.60 (s, 2H), 3.97 (s,3H), 3.70 (s, 3H), 3.08 (s, 3H).

The following examples were prepared in a manner analogous to that for3-(3-{[[5-(2-methoxypyridin-4-yl)-4-methyl-4H-1,2,4-triazol-3-yl](methyl)amino]methyl}-1,2,4-oxadiazol-5-yl)benzonitrile ExampleStructure No. Name ¹H-NMR

988 3-(3-{[methyl(4-methyl-5- pyridin-4-yl-4 H-1,2,4- triazol-3-yl)amino]methyl}-1,2,4- oxadiazol-5-yl)benzonitrile 8.41 (s, 1 H), 8.33(d, 2 H), 7.88 (d, 2 H), 7.71- 7.65 (m, 3 H), 4.61 (s, 2 H), 3.73 (s, 3H), 3.09 (s, 3 H).

989 3-(3-{[3-(2- methoxypyridin-4-yl)-6,7- dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5 H)- yl]methyl}-1,2,4- oxadiazol-5-yl)benzonitrile 8.40(s, 1 H), 8.32 (d, 1 H), 8.24 (d, 1 H), 7.86 (d, 1 H), 7.68 (t, 1 H),7.24 (d, 1 H), 6.97 (s, 1 H), 5.05 (s, 2 H), 4.13 (t, 2 H), 3.96 (s, 3H), 3.57 (t, 2 H), # 2.23 (m, 2 H).

990 N-{1-[5-(3-chlorophenyl)- 1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5- pyridin-4-yl-4 H-1,2,4- triazol-3-amine 8.72(d, 2 H) 8.09 (s, 1 H) 7.98 (d, 1 H) 7.62 (d, 2 H) 7.54 (d, 1 H) 7.44(t, 1 H) 4.85 (d, 1 H) 3.70 (s, 3 H) 2.95 (s, 3 H) 1.73 (d, 3 H)

Example 9913-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-3yl}benzonitrile

3-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]benzonitrile (98.2 mg, 0.447mmol), and3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine (62.2mg, 0.309 mmol) were suspended in acetonitrile (2 ml) and isopropanol(2.4 ml). After stirring for 45 min. potassium carbonate (88.1 mg, 0.637mmole) was added. The mixture was heated in a microwave oven (130° C.)for 30 min. The product was filtered and then purified on prep. HPLC togive 29 mg of the title compound. ¹H NMR (DMSO-d6): 8.72 (dd, 2H), 8.36(br t, 1H), 8.30 (dt, 1H), 8.08 (dt, 1H), 7.79 (t, 1H), 7.68 (dd, 2H),5.49 (s, 2H), 4.02 (t, 2H), 3.3 (m, 1H), 2.36 (s, 3H), 1.71 (t, 2H).

Example 9923-{5-[3-(2-Hydroxy-pyridin-4-yl)-6,7-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrimidin-8-ylmethyl]-[1,2,4]oxadiazol-3-yl}-benzonitrile

The title compound was synthesized analogous to3-{5-[(3-pyridin-4-yl-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl)methyl]-1,2,4-oxadiazol-3-yl}benzonitrile.¹H NMR: 8.34 (s, 1H), 8.29 (d, 1H), 7.79 (d, 1H), 7.67 (t, 1H), 7.38 (d,1H), 6.97 (m, 1H), 6.72 (s, 1H), 5.13 (s, 2H), 4.22 (m, 2H), 3.64 (m,2H), 2.27 (m, 2H).

Example 993N-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

1-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-ylmethyl]-1,2,3-trimethyl-isothiourea(55 mg, 0.177 mmol) was mixed with isonicotinic hydrazide (29.1 mg,0.212 mmol) in ethanol (1 mL) at 85° C. o.n. The reaction mixture wasdiluted with DCM and washed with water. The product was purified bycolumn chromatography with 5˜7% MeOH in EA and triturated with Et₂O togive the title compound (22.5 mg, 40%). ¹H-NMR: 8.80 (d, 2H), 8.10 (s,1H), 8.00 (d, 1H), 7.66 (d, 2H), 7.51 (d, 1H), 7.47 (t, 1H), 4.80 (s,2H), 3.74 (s, 3H), 3.15 (s, 3H).

The following examples were synthesized in a manner analogous to thatforN-{[3-(3-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amineExample Structure No. Name ¹H-NMR

994 N-{[3-(3- Chlorophenyl)- 1,2,4-oxadiazol- 5-yl]methyl}-4-cyclopropyl-N- methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine 8.75(d, 2 H), 8.09 (s, 1 H), 7.98 (d, 1 H), 7.77 (d, 2 H), 7.52 (d, 1 H),7.46 (t, 1 H), 4.95 (s, 2 H), 3.34 (m, 1 H), 3.32 (s, 3 H) 1.12 (m, 2 H)# and 0.95 (m, 2 H).

995 [3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]-ethyl-(4-methyl- 5-pyridin-4-yl- 4 H- [1,2,4]triazol-3- yl)-amine 8.74(d, 2 H), 8.01 (s, 1 H), 7.92 (d, 1 H), 7.62 (d, 2 H), 7.42 (d, 1 H),7.38 (t, 1 H), 4.78 (d, 2 H), 3.74 (d, 3 H), 3.41 (q, 2 H), 1.24 (t, 3H).

996 [3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-ylmethyl]-ethyl-(4-methyl- 5-pyridin-4-yl- 4 H- [1,2,4]triazol-3- yl)-amine 8.74(d, 2 H), 8 (s, 1 H), 7.89 (d, 1 H), 7.62 (d, 2 H), 7.44 (d, 1 H), 7.41(t, 1 H), 4.87 (s, 2 H), 3.76 (s, 3 H), 3.12 (m, 1 H), 0.82 (br, 2 H), #0.7 (br, 2 H).

997 N-{[3-(3- Chlorophenyl)- 1,2,4-oxadiazol- 5-yl]methyl}-N-isopropyl-4- methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine 8.79 (d,2 H), 8.01 (s, 1 H), 8.91 (d, 1 H), 7.68 (d, 2 H), 7.49 (d, 1 H), 7.44(t, 1 H), 4.82 (s, 2 H), 3.76 (s, 3 H), 3.60 (m, 1 H) and 1.35 (d, 6 H).

998 N-{1-[3-(3- Chlorophenyl)- 1,2,4-oxadiazol- 5-yl]-ethyl}-N-cyclopropyl-4- methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine 8.80(d, 2 H), 8.09 (s, 1 H), 7.99 (d, 1 H), 7.68 (d, 2 H), 7.52 (d, 1 H),7.47 (t, 1 H), 4.92 (q, 1 H), 3.71 (s, 3 H), 3.07 (m, 1 H), 1.87 # (d, 3H), 0.73 (m, 2 H), 0.55 (m, 1 H) and 0.42 (m, 1 H).

999 {1-[3-(3-Chloro- phenyl)- [1,2,4]oxadiazol- 5-yl]ethyl}- methyl-(4-methyl-5- pyridin-4-yl- 4 H- [1,2,4]triazol-3- yl)-amine 8.79 (d, 2 H),8.12 (s, 1 H), 8.02 (d, 1 H), 7.67 (d, 2 H), 7.5 (d, 1 H), 7.4 (t, 1 H),5.06 (q, 1 H), 3.73 (s, 3 H), 3.04 (s, 3 H), 1.87 (d, 3 H).

1000 [5-(3-Chloro- phenyl)- isoxazol-3- ylmethyl]- methyl-(4- methyl-5-pyridin-4-yl-4 H- [1,2,4]triazol-3- yl)-amine ¹H NMR (CDCl₃) d (ppm):8.79 (d, 2 H), 7.79 (m, 1 H), 7.66 (m, 3 H), 7.42 (m, 2 H), 6.83 (s, 1H), 4.59 (s, 2 H), 3.69 (s, 3 H), 3.00 (s, 3 H).

1001 N-{[5-(3- chlorophenyl)- 1,2,4-oxadiazol- 3-yl]methyl}-4-cyclopropyl-N- methyl-5- pyridin-4-yl-4 H- 1,2,4-triazol-3- amine

Example 1002N-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

n-BuLi (132 ml 2.5 M in hex., 0.33 mmol) was added to diisopropyl amine(55 ml, 0.39 mmol). After stirring for 20 minutes at 0° C. the mixturewas cooled to −78° C. andN-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine(110 mg, 0.28 mmol) was added. After 15 min. methyl iodide (20 VI, 0.33mmol) was added and the temperature was raised to r.t. After stirringfor 2 h five drops of water were added. After solvent removal in vacuo,the crude was taken up in DCM, washed with water and brine, dried andconcentrated. The desired product was obtained by prep. HPLC in 20 mgyield. ¹H NMR: 1.7 (s, 6H) 2.8 (s, 3H) 3.8 (s, 3H) 7.5 (t, 1H) 7.6 (d,1H) 7.7 (s, 2H) 8.0 (d, 1H) 8.1 (s, 1H) 8.8 (s, 2H)

Example 10034-(5-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]-1-methylethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine

To a solution of diisopropylamine (55.0 ml, 0.39 mmol) in THF (3 ml) at0° C. was added nBuLi (2.5M, hex., 135 ml) slowly. After 20 minutes themixture was cooled to −78° C. and(−)-4-(5-{(1R)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}-4-methyl-4H-1,2,4-triazol-3-yl)pyridine(107 mg, 0.28 mmol) in THF (2 ml) was added. The resulting mixture wasstirred for 45 minutes before CH₃I (22 ml, 0.34 mmol) was added and thereaction mixture was stirred for 1 h at r.t. Sat. NH₄Cl solution wasadded and the mixture was extracted with EA. The organic phase waswashed with H₂O and brine, dried and evaporated. Purification of theresidue by silica gel chromatography using CHCl₃:MeOH 50:1 followed byprep. HPLC gave the title compound (22 mg, 20%). ¹H-NMR: 2.11 (s, 6H)3.63 (s, 3H) 7.45 (d, 1H) 7.52-7.57 (m, 1H) 7.59 (d, 2H) 7.98 (d, 1H)8.09 (s, 1H) 8.72 (d, 2H)

Example 1004N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine

N-{(1S)-1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-N,4-dimethyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-amine(3.1 mg, 7.8 mmol) was incubated with human microsome protein (fromindividual with 70% 3A4) in 50% acetonitrile phosphate buffered at pH7.4 for 3 h and then concentrated under reduced pressure. The mixturewas extracted CHCl₃. The organic extract was dried and concentrated.Purification by prep. HPLC afforded 0.5 mg (16%) of the title compound.¹H NMR: 1.77-1.83 (d, 3H) 3.60 (s, 3H) 5.38-5.48 (m, 1H) 7.48 (m, 1H)7.54-7.62 (m, 2H) 8.01 (m, 1H) 8.12 (m, 1H) 8.74 (s, 2H).

Example 10055-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)methyl]-1,2,4-oxadiazol-3-amine

NaH (7.0 mg, 0.35 mmol) was added to a solution of5-(3-chlorophenyl)-N-methyl-1,2,4-oxadiazol-3-amine (60 mg, 0.29 mmol)in DMF (3 ml) at r.t. After 5 min4-[5-(chloromethyl)-4-methyl-4H-1,2,4-triazol-3-yl]pyridine (60 mg, 0.29mmol) dissolved in DMF (3 ml) was added. The reaction mixture wasstirred for 4 h at r.t. Aq. sat. NH₄Cl was added and the mixture wasextracted with EA. The organic phase was washed with water and brine,dried and concentrated. Flash chromatography (DCM/MeOH 20:1) afforded 60mg (54%) of the title compound. ¹H NMR: 3.12 (s, 3H) 3.80 (s, 3H) 4.94(s, 2H) 7.46 (t, 1H) 7.56 (m, 1H) 7.58-7.63 (m, 2H) 7.95 (m, 1H) 8.06(t, 1H) 8.79 (m, 2H).

Example 10065-(3-chlorophenyl)-N-ethyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)methyl]-1,2,4-oxadiazol-3-amine

The title compound was prepared analogous to5-(3-chlorophenyl)-N-methyl-N-[(4-methyl-5-pyridin-4-yl-4H-1,2,4-triazol-3-yl)methyl]-1,2,4-oxadiazol-3-amine.¹H NMR: 1.21 (t, 3H) 3.53 (q, 2H) 3.78 (s, 3H) 4.95 (s, 2H) 7.46 (d, 1H)7.53 (d, 1H) 7.59 (m, 2H) 7.95 (m, 1H) 8.05 (m, 1H) 8.77 (d, 2H).

Example 1007 Ethyl3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate

The title compound was prepared analogous to3-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole from ethyl2-oxopiperidine-3-carboxylate (2.57 g, 15 mmol), Me₃OBF₄ (2.66 g, 18mmol) and isonicotinic hydrazide (2.06 g, 15 mmol) in DCM (150 ml) andEtOH (16 ml). Recrystallization from EA afforded 1.67 g (41%). ¹H NMR:1.29 (t, 3H), 2.03 (m, 1H), 2.14-2.25 (m, 2H), 2.32 (m, 1H), 4.01-4.12(m, 1H), 4.16-4.27 (m, 4H), 7.64 (d, 2H), 8.74 (d, 2H)

Example 1008 3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole

5 drops of DMF was added to1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethanol (12.3 g, 54.9 mmol)in SOCl₂ (150 mL) and the reaction was heated at 70° C. for 5 h. Theexcess SOCl₂ was evaporated and the residue was purified by columnchromatography (Hep to Hep-EA 5:1) to give 12.4 g (93%) of the titlecompound. ¹H NMR: 1.96 (d, 3H) 5.20 (q, 1H) 7.46 (t, 1H) 7.59 (m, 1H)8.04 (m, 1H) 8.17 (t, 1H)

Example 1009 Ethyl8-{1-[5-(3-chlorophenyl)-1,2,4-oxadiazol-3-yl]ethyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridine-8-carboxylate

A solution of ethyl3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-α]pyridine-8-carboxylate(182 mg, 0.67 mmol) in DMF (2 ml) was added to a stirred mixture of NaH(20 mg, 0.81 mmol) in DMF (2 ml). After 45 min a solution of3-(1-chloroethyl)-5-(3-chlorophenyl)-1,2,4-oxadiazole (180 mg, 0.74mmol) in DMF (1 ml) was added and the resulting solution was stirred at65° C. for 3 h and then cooled to r.t. Aq. sat. NH₄Cl solution was addedand the mixture was extracted with EA. The organic phase was washed withwater and brine, dried and concentrated. Column chromatography (DCM/MeOH20:1) gave 207 mg (65%) of the title compound as a diastereomericmixture. ¹H NMR: 1.27 (t, 3H), 1.34 (t, 3H), 1.48 (d, 3H), 1.55 (d, 3H),2.15 (m, 2H), 2.18 (m, 4H), 2.61 (m, 2H), 4.00 (m, 2H), 4.18-4.29 (m,4H), 4.30-4.40 (m, 2H), 4.55 (q, 1H), 4.65 (q, 1H), 7.37 (t, 1H), 7.44(t, 1H), 7.50 (m, 1H), 7.55 (m, 1H), 7.63 (d, 2H), 7.69 (d, 2H), 7.83(m, 1H), 7.92 (m, 1H), 7.95 (m, 1H), 8.05 (m, 1H), 8.75 (d, 2H), 8.76(d, 2H)

Pharmaceutical Examples

FLIPR Assay of Group I Receptor Antagonist Activity

For FLIPR analysis, cells were seeded on collagen coated clear bottom96-well plates with black sides and analysis of [Ca²⁺]_(i) mobilizationwas performed 24 hours following seeding. Cell cultures in the 96-wellplates were loaded with a 4 μM solution of acetoxymethyl ester form ofthe fluorescent calcium indicator fluor-3 (Molecular Probes, Eugene,Oreg.) in 0.01% pluronic. All assays were performed in a buffercontaining 127 mM NaCl, 5 mM KCl, 2 mM MgCl₂, 0.7 mM NaH₂PO₄, 2 mMCaCl₂, 0.422 mg/ml NaHCO₃, 2.4 mg/ml HEPES, 1.8 mg/ml glucose and 1mg/ml BSA Fraction IV (pH 7.4).

FLIPR experiments were done using a laser setting of 0.800 W and a 0.4second CCD camera shutter speed with excitation and emission wavelengthsof 488 nm and 562 nm, respectively. Each FLIPR experiment was initiatedwith 160 μL of buffer present in each well of the cell plate. A 40 μLaddition from the antagonist plate was followed by a 50 μL addition fromthe agonist plate. After each addition the fluorescence signal wassampled 50 times at 1 second intervals followed by 3 samples at 5 secondintervals. Responses were measured as the peak height of the responsewithin the sample period.

EC₅₀/IC₅₀ determinations were made from data obtained from 8 pointconcentration response curves (CRC) performed in duplicate. Agonist CRCwere generated by scaling all responses to the maximal response observedfor the plate. Antagonist block of the agonist challenge was normalizedto the average response of the agonist challenge in 14 control wells onthe same plate.

Measurement of Inositol Phosphate (IP3) Turnover in Intact Whole Cells

GHEK stably expressing the human mGluR5d receptor were seeded onto 24well poly-L-lysine coated plates at 40×10⁴ cells/well in mediacontaining 1 μCi/well [3H] myo-inositol. Cells were incubated overnight(16 h), then washed three times and incubated for 1 hour at 37° C. inHEPES buffered saline (146 mM NaCl, 4.2 mM KCl, 0.5 mM MgCl₂, 0.1%glucose, 20 mM HEPES, pH 7.4) supplemented with 1 unit/ml glutamatepyruvate transaminase and 2 mM pyruvate. Cells were washed once in HEPESbuffered saline and pre-incubated for 10 minutes in HEPES bufferedsaline containing 10 mM LiCl. Compounds (agonists) were added andincubated at 37° C. for 30 minutes. Antagonist activity was determinedby pre-incubating test compounds for 15 minutes, then incubating in thepresence of glutamate (80 μM) or DHPG (30 μM) for 30 minutes. Thereaction was terminated by the addition of 0.5 ml perchloric acid (5%)on ice, with incubation at 4° C. for at least 30 minutes. Samples werecollected in 15 ml Falcon tubes and inositol phosphates were separatedusing Dowex columns, as described below.

Assay for Inositol Phosphates Using Gravity-Fed Ion-Exchange Columns

Preparation of Ion-Exchange Columns

Ion-exchange resin (Dowex AG1-X8 formate form, 200-400 mesh, BIORAD) waswashed three times with distilled water and stored at 4° C. 1.6 ml resinwas added to each column and washed with 3 ml 2.5 mM HEPES, 0.5 mM EDTA,pH 7.4.

Sample Treatment

Samples were collected in 15 ml Falcon tubes and neutralized with 0.375M HEPES, 0.75 M KOH. 4 ml of HEPES/EDTA (2.5/0.5 mM, pH 7.4) were addedto precipitate the potassium perchlorate. Supernatant was added to theprepared Dowex columns.

Inositol Phosphate Separation

Elute glycero phosphatidyl inositols with 8 ml 30 mM ammonium formate.

Elute total inositol phosphates with 8 ml 700 mM ammonium formate/100 mMformic acid and collect eluate in scintillation vials. Count eluatemixed with 8 ml scintillant.

Screening for Compounds Active Against TLESR

Adult Labrador retrievers of both genders, trained to stand in a Pavlovsling, are used. Mucosa-to-skin esophagostomies are formed and the dogsare allowed to recover completely before any experiments are done.

Motility Measurement

In brief, after fasting for approximately 17 h with free supply ofwater, a multilumen sleeve/sidehole assembly (Dentsleeve, Adelaide,South Australia) is introduced through the esophagostomy to measuregastric, lower esophageal sphincter (LES) and esophageal pressures. Theassembly is perfused with water using a low-compliance manometricperfusion pump (Dentsleeve, Adelaide, South Australia). An air-perfusedtube is passed in the oral direction to measure swallows, and anantimony electrode monitored pH, 3 cm above the LES. All signals areamplified and acquired on a personal computer at 10 Hz.

When a baseline measurement free from fasting gastric/LES phase IIImotor activity has been obtained, placebo (0.9% NaCl) or test compoundis administered intravenously (i.v., 0.5 ml/kg) in a foreleg vein. Tenmin after i.v. administration, a nutrient meal (10% peptone, 5%D-glucose, 5% Intralipid, pH 3.0) is infused into the stomach throughthe central lumen of the assembly at 100 ml/min to a final volume of 30ml/kg. The infusion of the nutrient meal is followed by air infusion ata rate of 500 ml/min until an intragastric pressure of 10±1 mmHg isobtained. The pressure is then maintained at this level throughout theexperiment using the infusion pump for further air infusion or forventing air from the stomach. The experimental time from start ofnutrient infusion to end of air insufflation is 45 min. The procedurehas been validated as a reliable means of triggering TLESRs.

TLESRs is defined as a decrease in lower esophageal sphincter pressure(with reference to intragastric pressure) at a rate of >1 mmHg/s. Therelaxation should not be preceded by a pharyngeal signal ≦2s before itsonset in which case the relaxation is classified as swallow-induced. Thepressure difference between the LES and the stomach should be less than2 mmHg, and the duration of the complete relaxation longer than 1 s.

Abbreviations

BSA Bovine Serum Albumin

CCD Charge Coupled Device

CRC Concentration Response Curve

DHPG 3,5-dihydroxyphenylglycine;

EDTA Ethylene Diamine Tetraacetic Acid

FLIPR Fluorometric Imaging Plate reader

GHEK GLAST-containing Human Embrionic Kidney

GLAST glutamate/aspartate transporter

HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (buffer)

IP₃ inositol triphosphate

Results

Typical IC₅₀ values as measured in the assays described above are 10 μMor less. In one aspect of the invention the IC₅₀ is below 2 μM. Inanother aspect of the invention the IC₅₀ is below 0.2 μM. In a furtheraspect of the invention the IC₅₀ is below 0.05 μM.

1. A compound selected from the group consisting the compounds set forthin the following table: 957

960

962

963

964

966

or a pharmaceutically acceptable salt thereof.

2-11. (canceled)
 12. A method of prevention and/or treatment of mGluR5receptor-mediated disorders, comprising administering to a mammal inneed of such prevention and/or treatment a therapeutically effectiveamount of a compound according to claim
 1. 13. The method according toclaim 12, wherein the disorder is a neurological disorder.
 14. Themethod according to claim 12, wherein the disorder is a psychiatricdisorder.
 15. The method according to claim 12, wherein the disorder isselected from chronic and acute pain disorders.
 16. The method accordingto claim 12, wherein the disorder is a gastrointestinal disorder. 17.The method according to claim 12, wherein the disorder is selected fromthe group consisting of Alzheimer's disease, senile dementia,AIDS-induced dementia, Parkinson's disease, amyotrophic lateralsclerosis, Huntington's Chorea, migraine, epilepsy, schizophrenia,depression, anxiety, acute anxiety, obsessive compulsive disorder,opthalmological disorders, diabetic retinopathies, glaucoma, auditoryneuropathic disorders, chemotherapy induced neuropathies, post-herpeticneuralgia and trigeminal neuralgia, tolerance, dependency, addiction andcraving disorders, neurodevelopmental disorders, autism, mentalretardation, schizophrenia, Down's Syndrome, pain related to migraine,inflammatory pain, neuropathic pain disorders, arthritis andrheumatitiod diseases, low back pain, post-operative pain, painassociated with angina, renal and billiary colic, menstruation, migrainegout, stroke, head trauma, anoxic and ischemic injuries, hypoglycemia,cardiovascular diseases and epilepsy.
 18. A method for inhibiting theactivation of mGluR5 receptors, comprising treating a cell containingsaid receptor with an effective amount of a compound according toclaim
 1. 19. A pharmaceutical formulation comprising as activeingredient a therapeutically effective amount of the compound accordingto claim 1 in association with one or more pharmaceutically acceptablediluents, excipients and/or inert carriers.